Protease inhibitors

ABSTRACT

This invention relates to compounds of formula (I):                    
     wherein: 
     Y is Ar or NR 1 R 2 ; 
     R 1  is R″, R″C(O), R″C(S), R″SO 2 , R″OC(O), R″R′NC(O), or R″R′NC(S); 
     R 2  is H, C 1-6 alkyl, C 2-6 alkenyl, Ar-C 0-6 alkyl, or Het-C 0-6 alkyl; 
     R 3  is H, C 2-6 alkenyl, C 2-6 alkynyl, Het, Ar or C 1-6 alkyl optionally substituted by OR′, SR′, NR′ 2 , N(R′)C(O)OR″, CO 2 R′, CO 2 NR′ 2 , N(C═NH)NH 2 , Het or Ar; 
     R 4  is H, C 1-6 alkyl, C 2-6 alkenyl, Ar-C 0-6 alkyl, or Het-C 0-6 alkyl; 
     R 5  is                    
      Ar-C 0-6 alkyl, Het-C 0-6 alkyl, adamantyl-C(O)—, Ar-C(O)—, Het-C(O)— or; 
     R 6  is R″, R″C(O), R″C(S), R″SO 2 , R″OC(O), R″R′NC(O), R″R′NC(S), or R″OC(O)NR′CH(R*)C(O); 
     R 7  is C 3-6 cycloalkyl-C 0-6 alkyl, Ar-C 0-6 alkyl, Het-C 0-6 alkyl, Ar-C 0-6 alkoxy, Het-C 0-6 alkoxy, or C 1-6 alkyl optionally substituted by OR′, SR′, NR′ 2 , N(R′)C(O)OR″, CO 2 R′, CO 2 NR′ 2 , N(C═NH)NH 2 , Het or Ar; 
     R* is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl-C 0-6 -alkyl, Ar-C 0-6 alkyl, Het-C 0-6 alkyl; 
     each R′ independently is H, C 1-6 alkyl, C 2-6 alkenyl, Ar-C 0-6 alkyl, or Het-C 0-6 alkyl; 
     each R″ independently is C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 -alkyl, Ar-C 0-6 alkyl, or Het-C 0-6 alkyl; 
     R′″ is H, C 1-6 alkyl, C 3-6 cycloalkyl-C 0-6 alkyl, Ar-C 0-6 alkyl, or Het-C 0-6 alkyl; 
     Z is C(O) or CH 2 ; and 
     n is 1, 2 or 3; 
     or a pharmaceutically acceptable salt thereof, which are inhibitors of cysteine proteases, particularly cathepsin K, and are useful in the treatment of diseases in which inhibition of bone loss is a factor.

This is a 371 of PCT/US98/09192, filed May 6, 1998 which claims benefitof Provisional Application No. 60/046,865, filed May 8, 1997.

FIELD OF THE INVENTION

This invention relates to novel protease inhibitors, particularlyinhibitors of cysteine and serine proteases, more particularly compoundswhich inhibit cysteine proteases, even more particularly compounds whichinhibit cysteine proteases of the papain superfamily, yet moreparticularly compounds which inhibit cysteine proteases of the cathepsinfamily, most particularly compounds which inhibit cathepsin K. Suchcompounds are particularly useful for treating diseases in whichcysteine proteases are implicated, especially diseases of excessive boneor cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.

BACKGROUND OF THE INVENTION

Cathepsin K is a member of the family of enzymes which are part of thepapain superfamily of cysteine proteases. Cathepsins B, H, L, N and Shave been described in the literature. Recently, cathepsin K polypeptideand the cDNA encoding such polypeptide were disclosed in U.S. Pat. No.5,501,969 (called cathepsin O therein). Cathepsin K has been recentlyexpressed, purified, and characterized. Bossard, M. J., et al., (1996)J. Biol. Chem. 271, 12517-12524; Drake, F. H., et al., (1996) J. Biol.Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271,2126-2132.

Cathepsin K has been variously denoted as cathepsin O, cathepsin X orcathepsin O2 in the literature. The designation cathepsin K isconsidered to be the more appropriate one (name assigned by NomenclatureCommittee of the International Union of Biochemistry and MolecularBiology).

Cathepsins of the papain superfamily of cysteine proteases function inthe normal physiological process of protein degradation in animals,including humans, e.g., in the degradation of connective tissue.However, elevated levels of these enzymes in the body can result inpathological conditions leading to disease. Thus, cathepsins have beenimplicated in various disease states, including but not limited to,infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma bruceibrucei, and Crithidia fusiculata; as well as in schistosomiasis malaria,tumor metastasis, metachromatic leukodystrophy, muscular dystrophy,amytrophy, and the like. See International Publication Number WO94/04172, published on Mar. 3, 1994, and references cited therein. Seealso European Patent Application EP 0 603 873 A1, and references citedtherein. Two bacterial cysteine proteases from P. gingivallis, calledgingipains, have been implicated in the pathogenesis of gingivitis.Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2,445-458.

Cathepsin K is believed to play a causative role in diseases ofexcessive bone or cartilage loss. Bone is composed of a protein matrixin which spindle- or plate-shaped crystals of hydroxyapatite areincorporated. Type I Collagen represents the major structural protein ofbone comprising approximately 90% of the structural protein. Theremaining 10% of matrix is composed of a number of non-collagenousproteins, including osteocalcin, proteoglycans, osteopontin,osteonectin, thrombospondin, fibronectin, and bone sialoprotein.Skeletal bone undergoes remodeling at discrete foci throughout life.These foci, or remodeling units, undergo a cycle consisting of a boneresorption phase followed by a phase of bone replacement.

Bone resorption is carried out by osteoclasts, which are multinuclearcells of hematopoietic lineage. The osteoclasts adhere to the bonesurface and form a tight sealing zone, followed by extensive membraneruffling on their apical (i.e., resorbing) surface. This creates anenclosed extracellular compartment on the bone surface that is acidifiedby proton pumps in the ruffled membrane, and into which the osteoclastsecretes proteolytic enzymes. The low pH of the compartment dissolveshydroxyapatite crystals at the bone surface, while the proteolyticenzymes digest the protein matrix. In this way, a resorption lacuna, orpit, is formed. At the end of this phase of the cycle, osteoblasts laydown a new protein matrix that is subsequently mineralized. In severaldisease states, such as osteoporosis and Paget's disease, the normalbalance between bone resorption and formation is disrupted, and there isa net loss of bone at each cycle. Ultimately, this leads to weakening ofthe bone and may result in increased fracture risk with minimal trauma.

The abundant selective expression of cathepsin K in osteoclasts stronglysuggests that this enzyme is essential for bone resorption. Thus,selective inhibition of cathepsin K may provide an effective treatmentfor diseases of excessive bone loss, including, but not limited to,osteoporosis, gingival diseases such as gingivitis and periodontitis,Paget's disease, hypercalcemia of malignancy, and metabolic bonedisease. Cathepsin K levels have also been demonstrated to be elevatedin chondroclasts of osteoarthritic synovium. Thus, selective inhibitionof cathepsin K may also be useful for treating diseases of excessivecartilage or matrix degradation, including, but not limited to,osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cellsalso typically express high levels of proteolytic enzymes that degradethe surrounding matrix. Thus, selective inhibition of cathepsin K mayalso be useful for treating certain neoplastic diseases.

It now has been discovered that a novel class of compounds are proteaseinhibitors, most particularly inhibitors of cathepsin K, and thesecompounds are useful for treating diseases in which inhibition of boneresorption is indicated, such as osteoporosis and periodontal disease.

SUMMARY OF THE INVENTION

An object of the present invention is to provide protease inhibitors,particularly such inhibitors of cysteine and serine proteases, moreparticularly such compounds which inhibit cysteine proteases, even moreparticularly such compounds which inhibit cysteine proteases of thepapain superfamily, yet more particularly such compounds which inhibitcysteine proteases of the cathepsin family, most particularly suchcompounds which inhibit cathepsin K, and which are useful for treatingdiseases which may be therapeutically modified by altering the activityof such proteases.

Accordingly, in the first aspect, this invention provides a compoundaccording to formula (I).

In another aspect, this invention provides a pharmaceutical compositioncomprising a compound according to formula (I) and a pharmaceuticallyacceptable carrier.

In yet another aspect, this invention provides a method of treatingdiseases in which the disease pathology may be therapeutically modifiedby inhibiting proteases, particularly cysteine and serine proteases,more particularly cysteine proteases, even more particularly cysteineproteases of the papain superfamily, yet more particularly cysteineproteases of the cathepsin family, most particularly cathepsin K.

In a particular aspect, the compounds of this invention are especiallyuseful for treating diseases characterized by bone loss, such asosteoporosis and gingival diseases, such as gingivitis andperiodontitis, or by excessive cartilage or matrix degradation, such asosteoarthritis and rheumatoid arthritis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula (I):

wherein:

Y is Ar or NR¹R²;

R¹ is R″, R″C(O), R″C(S), R″SO₂, R″OC(O), R″R′NC(O), or R″R′NC(S);

R² is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;

R³ is H, C₂₋₆alkenyl, C₂₋₆alkynyl, Het, Ar or C₁₋₆alkyl optionallysubstituted by OR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂, N(C═NH)NH₂,Het or Ar;

R⁴ is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;

R⁵ is

 Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl, adamantyl-C(O)—, Ar-C(O)—, or Het-C(O)—;

R⁶ is R″, R″C(O), R″C(S), R″SO₂, R″OC(O), R″R′NC(O), R″R′NC(S),orR″OC(O)NR′CH(R*)C(O);

R⁷ is C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl,Ar-C₀₋₆alkoxy, Het-C₀₋₆alkoxy, or C₁₋₆alkyl optionally substituted byOR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂, N(C═NH)NH₂, Het or Ar;

R* is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl,Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl;

each R′ independently is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl;

each R″ independently is C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl,Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;

R′″ is H, C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl;

Z is C(O) or CH₂; and

n is 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Preferably, the present invention provides compounds of formula (Ia):

wherein:

R¹ is R″, R″C(O), R″C(S), R″SO₂, R″OC(O), R″R′NC(O), or R″R′NC(S);

R² is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;

R³ is H, C₂₋₆alkenyl, C₂₋₆alkynyl, Het, Ar or C₁₋₆alkyl optionallysubstituted by OR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂, N(C═NH)NH₂,Het or Ar;

R⁴ is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;

R⁵ is

 Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl, adamantyl-C(O)—, Ar-C(O)—, or Het-C(O)—;

R⁶ is R″, R″C(O), R″C(S), R″SO₂, R″OC(O), R″R′NC(O), R″R′NC(S),orR″OC(O)NR′CH(R*)C(O);

R⁷ is C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl,Ar-C₀₋₆alkoxy, Het-C₀₋₆alkoxy, or C₁₋₆alkyl optionally substituted byOR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂, N(C═NH)NH₂, Het or Ar;

R* is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl,Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl;

each R′ independently is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl;

each R″ independently is C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl,Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;

R′″ is H, C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl;

Z is C(O) or CH₂; and

n is 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

The present invention includes all hydrates, solvates, complexes andprodrugs of the compounds of this invention. Prodrugs are any covalentlybonded compounds which release the active parent drug according toformula (I) in vivo. If a chiral center or another form of an isomericcenter is present in a compound of the present invention, all forms ofsuch isomer or isomers, including enantiomers and diastereomers, areintended to be covered herein. Inventive compounds containing a chiralcenter may be used as a racemic mixture, an enantiomerically enrichedmixture, or the racemic mixture may be separated using well-knowntechniques and an individual enantiomer may be used alone. In cases inwhich compounds have unsaturated carbon-carbon double bonds, both thecis (Z) and trans (E) isomers are within the scope of this invention. Incases wherein compounds may exist in tautomeric forms, such as keto-enoltautomers, each tautomeric form is contemplated as being included withinthis invention whether existing in equilibrium or predominantly in oneform.

The meaning of any substituent at any one occurrence in formula (I) orany subformula thereof is independent of its meaning, or any othersubstituent's meaning, at any other occurrence, unless specifiedotherwise.

With respect to formula (I):

Suitably, R⁴ and R′″ are each H and R³ is C₁₋₆alkyl or C₂₋₆alkenyl.Preferably, R³ is i-butyl.

Suitably, R⁵ is benzyl or

 in which R′is H, R⁷ is C₁₋₆alkyl, preferably i-butyl, R⁶ is R″OC(O),wherein R″ is benzyl, and Z is CH₂.

Suitably, Y is NR¹R², in which R² is H and R¹ is R″C(O) or R″OC(O), andR″ in said R¹ group is C₁₋₆alkyl, Ar-C₀₋₆alkyl or Het-C₀₋₆alkyl, and,most preferably, R″ is tert-butyl,

Suitably, n is 1 or 2. Preferably, n is 1.

In one particular embodiment, the formula (Ia) compound of thisinvention is a compound of formula (Ib):

In another embodiment, the formula (Ia) compound of this invention is acompound of formula (Ic):

Specific representative compounds of this invention are:

3-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

1-benzyl-3-[[N^(α)-(2quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

3-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

1-benzyl-3-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(benzyloxycarbonyl)-L-leuciny]amino]-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;

(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

1-benzyl-(3R)-[[N^(α)-(2-naphthyl)acetyl-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3R)-[[N^(α)-(2-naphtylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3R)-[[N^(α)-(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3R)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3R)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(2-naphthyl)acetyl-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(3-quinolinecarbonyl)-L-leucinyl]amino-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-4-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-piperidine;

1-benzyl-4-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-piperidine;

1-benzyl-4-[[N^(α)-(benzyloxycarbonyl)-L-leucinyl]amino]-piperidine;

1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(1-adamantanecarbonyl)-(3R)-[[N^(α)-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(1-adamantanecarbonyl)-(3S)-[[N^(α)-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;

(3R)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(benzothiazole-6-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(indole-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(4-fluorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(4-methoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(3,4-dichlorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(4-biphenylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3R)-[[N^(α)-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(benzothiazole-6-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(indole-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(4-fluorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(4-methoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(3,4-dichlorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(4-biphenylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

(3S)-[[N^(α)-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;

1-(4-phenyl)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenyl)benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenyl)benzyl-(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine,

1-(2-phenyl)ethyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-phenyl)ethyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-phenyl)ethyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-phenyl)ethyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-phenyl)ethyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-phenyl)ethyl-(3S)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-fluoro)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-fluoro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-fluoro)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-cyano)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-cyano)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino-pyrrolidine;

1-benzyl-(3S)-[[N^(α)-(3-(2-dimethylaminoethoxy)-4-methoxybenzoyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-(N,N-dimethylamino)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-methoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1]-(4-carboxymethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3,4-methylenedioxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-naphthyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-indolyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(1-naphthyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-pyrrolyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-acetamido)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-cyano)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-fluoro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-phenoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-chloro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-trifluoromethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-trifluoromethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-(3-(N,N-dimethylamino)propoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(4-(isopropyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-benzofuranyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-(3-methylbenzo[b]thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(2-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

-(3-thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

1-(3,4-dimethoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;and

1-(5-nitro-3-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;

or a pharmaceutically acceptable salt thereof.

In yet another aspect, this invention provides novel intermediatesuseful in the preparation of formula (I) compounds represented by theformula (II):

wherein:

R³ is H, C₂₋₆alkenyl, C₂₋₆alkynyl, Het, Ar or C₁₋₆alkyl optionallysubstituted by OR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂, N(C═NH)NH₂,Het or Ar;

R⁴ is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;

R⁵ is

 Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl, adamantyl-C(O)—, Ar-C(O)—, or Het-C(O)—;

R⁶ is R″, R″C(O), R″C(S), R″SO₂, R″OC(O), R″R′NC(O), R″R′NC(S),orR″OC(O)NR′CH(R*)C(O);

R⁷ is C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl,Ar-C₀₋₆alkoxy, Het-C₀₋₆alkoxy, or C₁₋₆alkyl optionally substituted byOR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂, N(C═NH)NH₂, Het or Ar;

R* is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl,Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl;

each R′ independently is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl;

each R″ independently is C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl,Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;

R′″ is H, C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl;

Z is C(O) or CH₂; and

n is 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Abbreviations and symbols commonly used in the peptide and chemical artsare used herein to describe the compounds of the present invention. Ingeneral, the amino acid abbreviations follow the IUPAC-IUB JointCommission on Biochemical Nomenclature as described in Eur. J. Biochem.,158, 9 (1984). The term “amino acid” as used herein refers to the D- orL-isomers of alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine and valine.

“C₁₋₆alkyl” as applied herein is meant to include substituted andunsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andt-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simplealiphatic isomers thereof. Any C₁₋₆alkyl group may be optionallysubstituted independently by one or two halogens, SR′, OR′, N(R′)₂,C(O)N(R′)₂, carbamyl or C₁₋₄alkyl, where R′ is H or C₁₋₆alkyl. C₀alkylmeans that no alkyl group is present in the moiety. Thus, Ar-C₀alkyl isequivalent to Ar.

“C₃₋₆cycloalkyl” as applied herein is meant to include substituted andunsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

“C₂₋₆ alkenyl” as applied herein means an alkyl group of 2 to 6 carbonswherein a carbon-carbon single bond is replaced by a carbon-carbondouble bond. C₂₋₆alkenyl includes ethylene, 1-propene, 2-propene,1-butene, 2-butene, isobutene and the several isomeric pentenes andhexenes. Both cis and trans isomers are included.

“C₂₋₆alkynyl” means an alkyl group of 2 to 6 carbons wherein onecarbon-carbon single bond is replaced by a carbon-carbon triple bond.C₂₋₆ alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne,2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.

“Halogen” or “halo” means F, Cl, Br, and I.

“Ar” or “aryl” means unsubstituted phenyl or naphthyl; or phenyl ornaphthyl substituted by one or more of Ph-C₀₋₆alkyl, Het-C₀₋₆alkyl,C₁₋₆alkoxy, Ph-C₀₋₆alkoxy, Het-C₀₋₆alkoxy, OH, (CH₂)₁₋₆NR′R′,O(CH₂)₁₋₆NR′R′; wherein each R′ independently is H, C₁₋₆alkyl,Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl; or phenyl or naphthyl substituted by oneto three moieties selected from C₁₋₄alkyl, OR′, N(R′)₂, SR′, CF₃, NO₂,CN, CO₂R′, CON(R′), F, Cl, Br and I, or substituted by a methylenedioxygroup.

As used herein “Het” or “heterocyclic” or “heteroaryl” represents astable 5- to 7-membered monocyclic or a stable 7- to 10-memberedbicyclic heterocyclic ring, which is either saturated or unsaturated,and which consists of carbon atoms and from one to four heteroatomsselected from the group consisting of N, O and S, and wherein thenitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen heteroatom may optionally be quaternized, and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure, and may optionally be substituted with one or two moietiesselected from C₁₋₄alkyl, OR′, N(R′)₂, SR′, CF₃, NO₂, CN, CO₂R′, CON(R′),F, Cl, Br and I, where R′ is as defined hereinbefore. Examples of suchheterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl,morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfone, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl,pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl,1,6-napthyridinyl, 1,7-napthyridinyl, 1,8-napthyridinyl, tetrazolyl,1,2,3-triazolyl, and 1,2,4-triazolyl. “Het” also means any heterocyclicmoiety encompassed by the above definition of Het which is aromatic incharacter, e.g., pyridinyl, quinolinyl, isoquinolinyl, pyrrolyl,pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzoxazolyl, furyl, thienyl, benzoxazolyl, oxadiazolyl,benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl,cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl,1,6-napthyridinyl, 1,7-napthyridinyl, 1,8-napthyridinyl, tetrazolyl,1,2,3-triazolyl, and 1,2,4-triazolyl.

Certain radical groups are abbreviated herein. t-Bu refers to thetertiary butyl radical, Boc or BOC refers to the t-butyloxycarbonylradical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refersto the phenyl radical, Cbz or CBZ refers to the benzyloxycarbonylradical.

Certain reagents are abbreviated herein. DCC refers todicyclohexylcarbodiimide, DMAP is 2,6-dimethylaminopyridine, EDC or EDCIrefers to N-ethyl-N′(dimethylaminopropyl)-carbodiimide. HOBT or HOBtrefers to 1-hydroxybenzotriazole, DMF refers to dimethyl formamide, BOPrefers to benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate, DMAP is dimethylaminopyridine, DIEA refers todi-isopropylethylamine, Lawesson's reagent is2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, NMMis N-methylmorpholine, TFA refers to trifluoroacetic acid, TFAA refersto trifluoroacetic anhydride, KHMDS refers to potassiumhexamethyldisilazide, and THF refers to tetrahydrofuran. Jones reagentis a solution of chromium trioxide, water, and sulfuric acid well-knownin the art.

Compounds of the formula (I) are generally prepared by reacting acompound of the formula (II):

or a salt thereof,

wherein R′″, R³, R⁴, R⁵ and n are as defined in formula (I), with anyreactive functional groups protected, with:

(a) R″C(O)Cl, in which R″ is as defined in formula (I) of claim 1; or

(b) R″C(O)OH, in which R″ is as defined in formula (I) of claim 1, inthe presence of EDC and HOBT; or

(c) R″C(O)H, in which R″ is as defined in formula (I) of claim 1,followed by reduction; or

(d) R″OC(O)Cl, in which R″is as defined in formula (I) of claim 1, inthe presence of base; or

(e) R″SO₂Cl, in which R″ is as defined in formula (I) of claim 1, in thepresence of base;

and thereafter removing any protecting groups and optionally forming apharmaceutically acceptable salt.

Compounds of the formula (I) are prepared by methods analogous to thosedescribed in Schemes 1 and 2.

a) PhCHO, CH₂Cl₂, NaBH(OAc)₃; b) HCl, EtOAc, CH₃OH; c) N-BOC-leucine,EDC, HOBt, NMM, CH₂Cl₂; d) HCl, EtOAc, CH₃OH; e) quinaldic acid, EDC,HOBt, NMM, CH₂Cl₂

Compounds of the general formula (1) wherein n is 1, R⁵ is an alkylgroup and R¹ is an R′C(O) can be prepared as outlined in Scheme 1.Reductive alkylation of the commercially available amine 1-Scheme-1(this material available in racemic or enantiomerically pure form) withan aldehyde, such as benzaldehyde or CBZ-leucinal, follwed by treatmentwith a reducing agent, such as sodium triacetoxyborohydride, affords thetertiary amine 2-Scheme-1. Removal of the protecting group by treating2-Scheme-1 with a strong acid, such as hydrogen chloride, in ethylacetate or ether or dioxane and methanol affords 3-Scheme-1. 3-Scheme-1may be coupled with an acid using EDC and HOBT in the presence of abase, such as N-methylmorpholine or triethylamine, in an aproticsolvent, such as dichloromethane, to yield 4-Scheme-1. The protectinggroup of 4-Scheme-1 may be removed with strong acid, such as hydrogenchloride, in ethyl acetate or ether or dioxane and methanol to afford5-Scheme-1. Coupling of the amine salt 5-Scheme-1 may be effected withan acid in the presence of EDC, HOBt and a base, such asN-methylmorpholine, to yield 6-Scheme-1. The 5-Scheme-1 salt may also beconverted to the sulphonamide derivative by treatment with a sulphonylchloride in the presence of a base, such as triethylamine, in an aproticsolvent, such as dichioromethane.

a) N-BOC-leucine, EDC, HOBT, NMM, CH₂Cl₂; b) HCl, EtOAc; c) 2-naphthoicacid, EDC, HOBT, CH₂Cl₂, NMM

Compounds of the general formula (I) wherein n is 2, R⁵ is a benzylgroup and R¹ is an R′ C(O) can be prepared as outlined in Scheme 1.Acylation of the commercially available 4-amino-1-benzylpiperidine(1-Scheme-1) with N-BOC-leucine in the presence of EDC, HOBT andN-methylmorpholine in dichloromethane afforded 2-scheme-2. Removal ofthe protecting group with anhydrous hydrogen chloride in ethyl acetateor ether or dioxane and methanol gave 3-Scheme-2. Acylation of the aminesalt 3-Scheme-2 with a carboxylic acid as described previously afforded4-Scheme-2.

The starting materials used herein are commercially available aminoacids or are prepared by routine methods well known to those of ordinaryskill in the art and can be found in standard reference books, such asthe COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published byWiley-Interscience).

Coupling methods to form amide bonds herein are generally well known tothe art. The methods of peptide synthesis generally set forth byBodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag,Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284(1979); and J. M. Stewart and J. D. Young, SOLID PHASE PEPTIDESYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984. aregenerally illustrative of the technique and are incorporated herein byreference.

Synthetic methods to prepare the compounds of this invention frequentlyemploy protective groups to mask a reactive functionality or minimizeunwanted side reactions. Such protective groups are described generallyin Green, T. W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley &Sons, New York (1981). The term “amino protecting groups” generallyrefers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivativesthereof as known to the art. Methods for protection and deprotection,and replacement of an amino protecting group with another moiety arewell known.

Acid addition salts of the compounds of formula (I) are prepared in astandard manner in a suitable solvent from the parent compound and anexcess of an acid, such as hydrochloric, hydrobromic, hydrofluoric,sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic ormethanesulfonic. Certain of the compounds form inner salts orzwitterions which may be acceptable. Cationic salts are prepared bytreating the parent compound with an excess of an alkaline reagent, suchas a hydroxide, carbonate or alkoxide, containing the appropriatecation; or with an appropriate organic amine. Cations such as Li⁺, Na⁺,K⁺, Ca⁺⁺, Mg⁺⁺ and NH₄ ⁺ are specific examples of cations present inpharmaceutically acceptable salts. Halides, sulfate, phosphate,alkanoates (such as acetate and trifluoroacetate), benzoates, andsulfonates (such as mesylate) are examples of anions present inpharmaceutically acceptable salts.

This invention also provides a pharmaceutical composition whichcomprises a compound according to formula (I) and a pharmaceuticallyacceptable carrier, diluent or excipient. Accordingly, the compounds offormula (I) may be used in the manufacture of a medicament.Pharmaceutical compositions of the compounds of formula (I) prepared ashereinbefore described may be formulated as solutions or lyophilizedpowders for parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation may be a buffered,isotonic, aqueous solution. Examples of suitable diluents are normalisotonic saline solution, standard 5% dextrose in water or bufferedsodium or ammonium acetate solution. Such formulation is especiallysuitable for parenteral administration, but may also be used for oraladministration or contained in a metered dose inhaler or nebulizer forinsufflation. It may be desirable to add excipients such aspolyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethyleneglycol, mannitol, sodium chloride or sodium citrate.

Alternately, these compounds may be encapsulated, tableted or preparedin an emulsion or syrup for oral administration. Pharmaceuticallyacceptable solid or liquid carriers may be added to enhance or stabilizethe composition, or to facilitate preparation of the composition. Solidcarriers include starch, lactose, calcium sulfate dihydrate, terra alba,magnesium stearate or stearic acid, talc, pectin, acacia, agar orgelatin. Liquid carriers include syrup, peanut oil, olive oil, salineand water. The carrier may also include a sustained release materialsuch as glyceryl monostearate or glyceryl distearate, alone or with awax. The amount of solid carrier varies but, preferably, will be betweenabout 20 mg to about 1 g per dosage unit. The pharmaceuticalpreparations are made following the conventional techniques of pharmacyinvolving milling, mixing, granulating, and compressing, when necessary,for tablet forms; or milling, mixing and filling for hard gelatincapsule forms. When a liquid carrier is used, the preparation will be inthe form of a syrup, elixir, emulsion or an aqueous or non-aqueoussuspension. Such a liquid formulation may be administered directly p.o.or filled into a soft gelatin capsule.

For rectal administration, the compounds of this invention may also becombined with excipients such as cocoa butter, glycerin, gelatin orpolyethylene glycols and molded into a suppository.

The compounds of formula (I) are useful as protease inhibitors,particularly as inhibitors of cysteine and serine proteases, moreparticularly as inhibitors of cysteine proteases, even more particularlyas inhibitors of cysteine proteases of the papain superfamily, yet moreparticularly as inhibitors of cysteine proteases of the cathepsinfamily, most particularly as inhibitors of cathepsin K. The presentinvention also provides useful compositions and formulations of saidcompounds, including pharmaceutical compositions and formulations ofsaid compounds.

The present compounds are useful for treating diseases in which cysteineproteases are implicated, including infections by pneumocystis carinii,trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as wellas in schistosomiasis, malaria, tumor metastasis, metachromaticleukodystrophy, muscular dystrophy, amytrophy; and especially diseasesin which cathepsin K is implicated, most particularly diseases ofexcessive bone or cartilage loss, including osteoporosis, gingivaldisease including gingivitis and periodontitis, arthritis, morespecifically, osteoarthritis and rheumatoid arthritis, Paget's disease;hypercalcemia of malignancy, and metabolic bone disease.

Metastatic neoplastic cells also typically express high levels ofproteolytic enzymes that degrade the surrounding matrix, and certaintumors and metastatic neoplasias may be effectively treated with thecompounds of this invention.

The present invention also provides methods of treatment of diseasescaused by pathological levels of proteases, particularly cysteine andserine proteases, more particularly cysteine proteases, even moreparticularly as inhibitors of cysteine proteases of the papainsuperfamily, yet more particularly cysteine proteases of the cathepsinfamily, which methods comprise administering to an animal, particularlya mammal, most particularly a human in need thereof a compound of thepresent invention. The present invention especially provides methods oftreatment of diseases caused by pathological levels of cathepsin K,which methods comprise administering to an animal, particularly amammal, most particularly a human in need thereof an inhibitor ofcathepsin K, including a compound of the present invention. The presentinvention particularly provides methods for treating diseases in whichcysteine proteases are implicated, including infections by pneumocystiscarinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata;as well as in schistosomiasis, malaria, tumor metastasis, metachromaticleukodystrophy, muscular dystrophy, amytrophy, and especially diseasesin which cathepsin K is implicated, most particularly diseases ofexcessive bone or cartilage loss, including osteoporosis, gingivaldisease including gingivitis and periodontitis, arthritis, morespecifically, osteoarthritis and rheumatoid arthritis, Paget's disease,hypercalcemia of malignancy, and metabolic bone disease.

This invention further provides a method for treating osteoporosis orinhibiting bone loss which comprises internal administration to apatient of an effective amount of a compound of formula (I), alone or incombination with other inhibitors of bone resorption, such asbisphosphonates (i.e., allendronate), hormone replacement therapy,anti-estrogens, or calcitonin. In addition, treatment with a compound ofthis invention and an anabolic agent, such as bone morphogenic protein,iproflavone, may be used to prevent bone loss or to increase bone mass.

For acute therapy, parenteral administration of a compound of formula(I) is preferred. An intravenous infusion of the compound in 5% dextrosein water or normal saline, or a similar formulation with suitableexcipients, is most effective, although an intramuscular bolus injectionis also useful. Typically, the parenteral dose will be about 0.01 toabout 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner tomaintain the concentration of drug in the plasma at a concentrationeffective to inhibit cathepsin K. The compounds are administered one tofour times daily at a level to achieve a total daily dose of about 0.4to about 400 mg/kg/day. The precise amount of an inventive compoundwhich is therapeutically effective, and the route by which such compoundis best administered, is readily determined by one of ordinary skill inthe art by comparing the blood level of the agent to the concentrationrequired to have a therapeutic effect.

The compounds of this invention may also be administered orally to thepatient, in a manner such that the concentration of drug is sufficientto inhibit bone resorption or to achieve any other therapeuticindication as disclosed herein. Typically, a pharmaceutical compositioncontaining the compound is administered at an oral dose of between about0.1 to about 50 mg/kg in a manner consistent with the condition of thepatient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.

No unacceptable toxicological effects are expected when compounds of thepresent invention are administered in accordance with the presentinvention.

The compounds of this invention may be tested in one of severalbiological assays to determine the concentration of compound which isrequired to have a given pharmacological effect.

Determination of Cathepsin K Proteolytic Catalytic Activity

All assays for cathepsin K were carried out with human recombinantenzyme. Standard assay conditions for the determination of kineticconstants used a fluorogenic peptide substrate, typicallyCbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions wereprepared at concentrations of 10 or 20 mM in DMSO with 20 uM finalsubstrate concentration in the assays. All assays contained 10% DMSO.Independent experiments found that this level of DMSO had no effect onenzyme activity or kinetic constants. All assays were conducted atambient temperature. Product fluorescence (excitation at 360 nM;emission at 460 nM) was monitored with a Perceptive Biosystems CytofluorII fluorescent plate reader. Product progress curves were generated over20 to 30 minutes following formation of AMC product.

Inhibition Studies

Potential inhibitors were evaluated using the progress curve method.Assays were carried out in the presence of variable concentrations oftest compound. Reactions were initiated by addition of enzyme tobuffered solutions of inhibitor and substrate. Data analysis wasconducted according to one of two procedures depending on the appearanceof the progress curves in the presence of inhibitors. For thosecompounds whose progress curves were linear, apparent inhibitionconstants (K_(i,app)) were calculated according to equation 1 (Brandt etal., Biochemitsry, 1989, 28, 140):

v 32 V _(m) A/[K _(a)(1+I/K _(i, app))+A]  (1)

where v is the velocity of the reaction with maximal velocity V_(m), Ais the concentration of substrate with Michaelis constant of K_(a), andI is the concentration of inhibitor.

For those compounds whose progress curves showed downward curvaturecharacteristic of time-dependent inhibition, the data from individualsets was analyzed to give k_(obs) according to equation 2:

[AMC]=v _(ss) t+(v ₀ −v _(ss))[1−exp(−k _(obs) t)]/k _(obs)  (2)

where [AMC] is the concentration of product formed over time t, v₀ isthe initial reaction velocity and v_(ss) is the final steady state rate.Values for k_(obs) were then analyzed as a linear function of inhibitorconcentration to generate an apparent second order rate constant(k_(obs)/inhibitor concentration or k_(obs)/[I]) describing thetime-dependent inhibition. A complete discussion of this kinetictreatment has been fully described (Morrison et al., Adv. Enzymol.Relat. Areas Mol. Biol., 1988, 61, 201).

One skilled in the art would consider any compound with a K_(i) of lessthan 50 micromolar to be a potential lead compound. Preferably, thecompounds used in the method of the present invention have a K_(i) valueof less than 1 micromolar. Most preferably, said compounds have a K_(i)value of less than 100 nanomolar.4-(R,S)-Amino-N-[(8-quinolinesulfonyl)-S-leucine]-3-tetrahydrofuran-3-one,a compound of formula (I), has a K_(i) value that is greater than 10micromolar.

Human Osteoclast Resorption Assay

Aliquots of osteoclastoma-derived cell suspensions were removed fromliquid nitrogen storage, warmed rapidly at 37° C. and washed ×1 inRPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4° C.). Themedium was aspirated and replaced with murine anti-HLA-DR antibody,diluted 1:3 in RPMI-1640 medium, and incubated for 30 min on ice Thecell suspension was mixed frequently.

The cells were washed ×2 with cold RPMI-1640 by centrifugation (1000rpm, 5 min at 4° C.) and then transferred to a sterile 15 mL centrifugetube. The number of mononuclear cells were enumerated in an improvedNeubauer counting chamber.

Sufficient magnetic beads (5/mononuclear cell), coated with goatanti-mouse IgG, were removed from their stock bottle and placed into 5mL of fresh medium (this washes away the toxic azide preservative). Themedium was removed by immobilizing the beads on a magnet and is replacedwith fresh medium.

The beads were mixed with the cells and the suspension was incubated for30 min on ice. The suspension was mixed frequently. The bead-coatedcells were immobilized on a magnet and the remaining cells(osteoclast-rich fraction) were decanted into a sterile 50 mL centrifugetube. Fresh medium was added to the bead-coated cells to dislodge anytrapped osteoclasts. This wash process was repeated ×10. The bead-coatedcells were discarded.

The osteoclasts were enumerated in a counting chamber, using alarge-bore disposable plastic pasteur pipette to charge the chamber withthe sample. The cells were pelleted by centrifugation and the density ofosteoclasts adjusted to 1.5×10⁴/mL in EMEM medium, supplemented with 10%fetal calf serum and 1.7 g/liter of sodium bicarbonate. 3 mL aliquots ofthe cell suspension (per treatment) were decanted into 15 mL centrifugetubes. These cells were pelleted by centrifugation. To each tube 3 mL ofthe appropriate treatment was added (diluted to 50 uM in the EMEMmedium). Also included were appropriate vehicle controls, a positivecontrol (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2adiluted to 100 ug/mL). The tubes were incubate at 37° C. for 30 min.

0.5 mL aliquots of the cells were seeded onto sterile dentine slices ina 48-well plate and incubated at 37° C. for 2 h. Each treatment wasscreened in quadruplicate. The slices were washed in six changes of warmPBS (10 mL/well in a 6-well plate) and then placed into fresh treatmentor control and incubated at 37° C. for 48 h. The slices were then washedin phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2Msodium cacodylate) for 5 min., following which they were washed in waterand incubated in buffer for 5 min at 37° C. The slices were then washedin cold water and incubated in cold acetate buffer/fast red garnet for 5min at 4° C. Excess buffer was aspirated, and the slices were air driedfollowing a wash in water.

The TRAP positive osteoclasts were enumerated by bright-field microscopyand were then removed from the surface of the dentine by sonication. Pitvolumes were determined using the Nikon/Lasertec ILM21W confocalmicroscope.

EXAMPLES

Nuclear magnetic resonance spectra were recorded at either 250 or 400MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.CDCl₃ is deuteriochloroform, DMSO-d₆ is hexadeuteriodimethylsulfoxide,and CD₃OD is tetradeuteriomethanol. Chemical shifts are reported inparts per million (d) downfield from the internal standardtetramethylsilane. Abbreviations for NMR data are as follows: s=singlet,d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets,dt=doublet of triplets, app=apparent, br=broad. J indicates the NMRcoupling constant measured in Hertz. Continuous wave infrared (IR)spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, andFourier transform infrared (FTIR) spectra were recorded on a NicoletImpact 400 D infrared spectrometer. IR and FTIR spectra were recorded intransmission mode, and band positions are reported in inversewavenumbers (cm⁻¹). Mass spectra were taken on either VG 70 FE, PE SyxAPI III, or VG ZAB HF instruments, using fast atom bombardment (FAB) orelectrospray (ES) ionization techniques. Elemental analyses wereobtained using a Perkin-Elmer 240C elemental analyzer. Melting pointswere taken on a Thomas-Hoover melting point apparatus and areuncorrected. All temperatures are reported in degrees Centigrade (° C.).

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layerplates were used for thin layer chromatography. Both flash and gravitychromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh)silica gel.

Where indicated, certain of the materials were purchased from theAldrich Chemical Co., Milwaukee, Wis., Chemical Dynamics Corp., SouthPlainfield, N.J., and Advanced Chemtech, Louisville, Ky.

Unless otherwise indicated, all of the starting materials were obtainedfrom commercial sources. Without further elaboration, it is believedthat one skilled in the art can, using the preceding description,utilize the present invention to its fullest extent. These Examples aregiven to illustrate the invention, not to limit its scope. Reference ismade to the claims for what is reserved to the inventors hereunder.

Example 1 Preparation of3-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinea.)3-[(tert-butoxycarbonyl)amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

To a solution of 3-(tert-butoxycarbonylamino)pyrrolidine (2.0 g, 10.74mmol) in CH₂Cl₂ was added CBZ-leucinal (3.2 g, 12.88 mmol). The reactionwas allowed to stir at room temperature for approximately 1 hourwhereupon sodium triacetoxyborohydride (3.4 g, 16.11 mmol) was added ina single portion. The reaction was stirred an additional 2 hourswhereupon it was diluted with ethyl acetate and washed with sat'dNaHCO3, brine, dried (Na₂SO₄), concentrated and chromatographed (5%CH₃OH:CH₂Cl₂) to give 4.3 g of the title compound: MS(ES+) 420 (MH⁺).

b.)3-amino-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinebis hydrochloride

To a solution of the compound of Example 1(a) (4.3 g) in CH₃OH (10 mL)was added 4M HCl in dioxane (10 mL). The reaction was stirred at roomtemperature for 4 hours whereupon it was concentrated in vacuo to yield3.97 g of the title compound: MS(ES+) 320 (MH⁺).

c.)3-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

To a solution of the compound of Example 1(b) (2.0 g, 5.1 mmole) wasadded EDC (1.27 g, 6.37 mmol) HOBT (724 mg, 5.35 mmol) TEA (1.78 mL,12.75 mmol) and N-BOC-leucine (1.3 g, 5.35 mmol) The reaction wasstirred until complete as indicated by TLC analysis whereupon it wasdiluted with ethyl acetate and washed with 5% NaHCO₃, brine, dried(MgSO₄), filtered, concentrated and chromatographed (5% CH₃OH:CH₂Cl₂) togive 2.7 g of the title compound: MS(ES+) 533 (MH⁺)

d.)3-L-leucinyl-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinebis hydrochloride

Following the procedure of Example 1(b) except substituting the compoundof Example 1(c), the title compound was produced: MS(ES+) 433 (MH⁺).

e.)3-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(c) except substituting the compoundof Example 1(d) and quinaldic acid for N-BOC-leucine, the title compoundwas produced: MS(ES+) 588 (MH⁺).

Example 2 Preparation of1-benzyl-3-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidinea.)1-benzyl-3-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 1(c) except substituting1-benzyl-3-aminopyrrolidine, the title compound was prepared. MS(ES+)390 (MH⁺).

b.) 1-benzyl-3-L-leucinyl-pyrrolidine bis hydrochloride

Following the procedure of Example 1(b) except substituting the compoundof Example 2(a), the title compound was prepared: MS(ES+) 290 (MH⁺).

c.)1-benzyl-3-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 1(e) except substituting the compoundof Example 2(b), the title compound was prepared: MS(ES+) 445 (MH⁺).

Example 3 Preparation of3-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(e) except substituting 2-naphthoicacid for quinaldic acid, the title compound was prepared: MS(ES+) 587(MH+).

Example 4 Preparation of1-benzyl-3-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 2(c) except substituting 2-naphthoicacid for quinaldic acid, the title compound was produced: MS(ES+) 444(MH⁺).

Example 5 Preparation of1-benzyl-((3S))-[[N^(α)-(benzyloxycabonyl)-L-leucinyl]amino]-pyrrolidinea.) 1-benzyl-((3S))-(tert-butoxycarbonyl)amino-pyrrolidine

Following the procedure of Example 1(a) except substituting((3S))-(−)-3-(tert-butoxycarbonylamino)pyrrolidine for3-(tert-butoxycarbonylamino)pyrrolidine and benzaldehyde forCBZ-leucinal, the title compound was prepared: MS(ES+) 221.2 (M-C₄H₈),277.3 (MH⁺).

b.) 1-benzyl-((3S))-amino-pyrrolidine bis hydrochloride

To a solution of the compound of Example 5(a) in methanol was added a 1MHCl/ether. The reaction was stirred at room temperature until completeas indicated by mass spectral analysis. The reaction was concentrated invacuo to give a white solid: MS(ES+) 177.0 (MH⁺).

c.)1-benzyl-((3S))-[[N^(α)-(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 1(c) except substituting the compoundof Example 5(b) and CBZ-leucine for BOC-leucine, the title compound wasprepared: MS(ES+) 424.2(MH⁺).

Example 6 Preparation of1-benzyl-((3S))-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 5(c) except substituting BOC-leucinefor CBZ-leucine, the title compound was prepared: MS(ES+) 390.5 (MH⁺).

Example 7 Preparation of((3S))-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinea.)((3S))-[(tert-butoxycarbonyl)amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(a) except substituting((3S))-(−)-3-(tert-butoxycarbonylamino)pyrrolidine for3-(tert-butoxycarbonylamino)pyrrolidine the title compound was prepared:MS(ES+) 420 (MH⁺).

b.)((3S))-[(tert-butoxycarbonyl)amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(b) except substituting the compoundof Example 7(a), the title compound was produced: MS(ES) 320 (MH⁺)

c.)(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(c) except substituting the compoundof Example 7(b), the title compound was produced: MS(ES+) 533 (MH⁺).

d.)(3S)-L-leucinyl-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinebis hydrochloride

Following the procedure of Example 1(d) except substituting the compoundof Example 7(c), the title compound was prepared: MS(ES+) 433 (MH⁺).

e.)(3S)-[[N^(α)-(2-naphythylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(e) except substituting the compoundof Example7(d) and substituting 2-naphthoic acid for quinaldic acid, thetitle compound was produced: MS(ES+) 587 (MH⁺).

Example 8 Preparation of(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinea.)(3R)-[(tert-butoxycarbonyl)amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(a) except substituting(3R)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine for3-(tert-butoxycarbonylamino)pyrrolidine the title compound was prepared:MS(ES+) 420 (MH⁺).

b.)(3R)-amino-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(b) except substituting the compoundof Example 8(a), the title compound was produced: 320 MS(ES) (MH⁺)

c.)(3R)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(c) except substituting the compoundof Example 8(b), the title compound was produced: 533 MS(ES+) (MH⁺).

d.)(3R)-L-leucinyl-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinebis hydrochloride

Following the procedure of Example 1(d) except substituting the compoundof Example 8(c), the title compound was prepared: MS(ES+) 433 (MH⁺).

e.)(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(e) except substituting the compoundof Example 8(d) and substituting 2-naphthoic acid for quinaldic acid,the title compound was produced: MS(ES+) 587 (MH⁺).

Example 9 Preparation of1-benzyl-(3R)-[[N^(α)-(2-quinolineacetonoyi)-L-leucinyl]amino]-pyrrolidinea.) 1-benzyl-(3R)-[(tert-butoxycarbonyl)amino]-pyrrolidine

To a solution of ((3R))-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (2.0g, 10.73 mmol) in CH₂Cl₂ (20 mL) was added benzaldehyde (1.3 mL, 12.88mmol). The reaction was stirred at room temperature for 2 hourswhereupon sodium triacetoxyborohydride (5.68 g, 26.82 mmol) was added.The reaction was stirred overnight at room temperature whereupon it wasdiluted with ethyl acetate and washed with sat. K₂CO₃, water, brine,dried (MgSO₄), filtered, concentrated and chromatographed (1:1hex:EtOAc) to give the title compound: MS(ES+) 221.1 (M-C₄H₈), 277.2(MH⁺)

b.) 1-benzyl-(3R)-amino-pyrrolidine bis hydrochloride

To a solution of the compound of Example 9(a) in methanol was added 1NHCl/ether. The suspension was stirred at room temperature until completeas indicated by mass spectral analysis. The reaction was concentrated invacuo to give the title compound: MS(ES+) 176.9 (MH⁺).

c).1-benzyl-(3R)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 1(c) except substituting the compoundof Example 9(b) and N-methylmorpholine for triethylamine, the titlecompound was produced: MS(ES+) 390.3 (MH⁺).

d.) 1-benzyl-(3R)-[(L-leucinyl]amino]-pyrrolidine bis hydrochloride

To a solution of the compound of Example 9(c) in ethyl acetate andmethanol was bubbled HCl gas for ca. 2 mins. The reaction was stirredovernight whereupon it was concentrated in vacuo to afford the titlecompound: MS(ES+) 290.4 (MH⁺).

e.)1-benzyl-(3R)-[[N^(α)-(2-naphthylacetonoyl)-L-leucinyl]amino]-pyrrolidine

To a suspension of the compound of Example 9(d) (75 mg) was added EDC(44.3 mg), HOBT (28.4 mg) NMM (0.14 mL) and 2-naphthylacetic acid. Thereaction was stirred overnight at room temperature whereupon it wasdiluted wiyh ethyl acetae and washed with sat. K₂CO₃, water, brine,dried (MgSO₄), filtered, concentrated and chromatographed to give thetitle compound: MS(ES+) 458.3 (MH+).

Example 10 Preparation of1-benzyl-(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 9(e) except substituting 2-naphthoicacid for 2-naphthylacetic acid, the title compound was prepared: MS(ES+)444.2 (MH⁺).

Example 11 Preparation of1-benzyl-(3R)-[[N^(α)-(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 9(e) except substituting3-quinolinecarboxylic acid for 2-naphthylacetic acid, the title compoundwas prepared: MS(ES+) 445.3 (MH⁺).

Example 12 Preparation of1-benzyl-(3R)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 9(e) except substituting quinaldicacid for 2-naphthylacetic acid, the title compound was prepared: MS(ES+)445.2 (MH⁺).

Example 13 Preparation of1-benzyl-(3R)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 9(e) except substituting3-isoquinolinecarboxylic acid for 2-naphthylacetic acid, the titlecompound was prepared: MS(ES+) 445.3 (MH⁺).

Example 14 Preparation of1-benzyl-(3S)-[[N^(α)-(2-naphthylacetonoyl)-L-leucinyl]amino]-pyrrolidinea.) 1-benzyl-(3S)-[(tert-butoxycarbonyl)amino]-pyrrolidine

Following the procedure of Example 9(a) except substituting((3S))-(−)-3-(tert-butoxycarbonylamino)pyrrolidine for(3R)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, the title compound wasproduced: MS(ES+) 277.2 (MH⁺).

b.) 1-benzyl-(3S)-amino-pyrrolidine bis hydrochloride

Following the procedure of Example 9(b) except substituting the compoundof example 14(a), the title compound was produced: MS(ES+) 177.0 (MH⁺).

c.)1-benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 9(c) except substituting the compoundof Example 14(b), the title compound was produced: MS(ES+) 390.3 (MH⁺).

d.) 1-benzyl-(3S)-[(L-leucinyl]amino]-pyrrolidine bis hydrochloride

Following the procedure of Example 9(d) except substituting the compoundof Example 14(c), the title compound was produced: MS(ES+) 290.3 (MH⁺).

e.)1-benzyl-(3S)-[[N^(α)-(2-naphthylacetonoyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 9(e) except substituting the compoundof Example 14(d), the title compound was produced: MS(ES+) 458.4 (MH⁺).

Example 15 Preparation of1-benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 14(e) except substituting 2-naphthoicacid for 2-naphthylacetic acid, the title compound was produced: MS(ES+)444.4 (MH⁺).

Example 16 Preparation of1-benzyl-(3S)-[[N^(α)-(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 14(e) except substituting3-quinolinecarboxylic acid for 2-naphthylacetic acid, the title compoundwas produced: MS(ES+) 445.2 (MH⁺).

Example 17 Preparation of1-benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 14(e) except substituting quinaldicacid for 2-naphthylacetic acid, the title compound was produced: MS(ES+)445.3 (MH⁺).

Example 18 Preparation of1-benzyl-(3S)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 14(e) except substituting3-isoquinolinecarboxylic acid for 2-naphthylacetic acid, the titlecompound was produced: MS(ES+) 445.3 (MH⁺).

Example 19 Preparation of1-benzyl-4-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-piperidine a.)1-benzyl-4-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-piperidine

Following the procedure of Example 1(c) except substituting4-amino-1-benzylpiperidine, the title compound was produced: MS(ES+)404.1 (MH⁺).

b.) 1-benzyl-4-[(L-leucinyl]amino]-piperidine

The compound of Example 19(a) (2.0 g) was dissolved in 4N HCl/dioxane(100 mL). The reaction was stirred at room temperature for 30 minuteswhereupon it was concentrated in vacuo to give 1.94 g of the titlecompound as a white solid: MS(ES+) 304.2 (MH⁺).

c.) 1-benzyl-4-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-piperidine

To a solution of the compound of Example 19(b) (240 mg) in DMF (3.0 mL)was added N-methylmorpholine (0.17 mL), HOBT (101.5 mg), 2-naphthoicacid (130.2 mg) and EDC (145.4 mg). The reaction was stirred overnightwhereupon it was poured into a rapidly stirred mixture of EtOAc, 10%Na₂CO₃ and brine (75 mL each). This mixture was stirred for 30 minutes.The organic layer was sepaerated and the aqueous layer was washed withethyl acetate. The combined organic layers were washed with 10% Na₂CO₃,water, brine, dried (MgSO₄), filtered, concentrated and chromatographed(ethyl acetate) to give 107 mg of the title compound: MS(ES+) 458.5(MH⁺).

Example 20 Preparation of1-benzyl-4-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-piperidine

Following the procedure of Example 19(c) except substituting quinaldicacid for 2-naphthoic acid, the title compound was prepared: MS(ES+)459.3 (MH⁺).

Example 21 Preparation of1-benzyl-4-[[N^(α)-(benzyloxycarbonyl)-L-leucinyl]amino]-piperidine

To a solution of N-benzyl-4-amino piperidine (0.50 g) in CH₂Cl₂ (10 mL)was added CBZ-leucine (695 mg), EDC (552.5 mg) and HOBT (356.6 mg). Thereaction was stirred at room temperature until complete as indicated byTLC analysis. The reaction was dissolved in CHCl₃ and washed with 10%Na₂CO₃, brine, dried (MgSO₄), filtered, concentrated and chromatographed(3:1 EtOAc:hexanes) to give 0.99 g of the title compound: MS(ES+) 438(MH⁺).

Example 22 Preparation of1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea) N-methyl-N-methoxy-3-(2-pyridyl)-phenylacetamide

To a stirred solution of N-methoxy-N-methylamine hydrochloride (0.980 g,10.0 mmol) in DMF (25 mL) was added N-methylmorpholine (1.21 mL, 11.0mmol), HOBt (1.50 g, 11.1 mmol), 3-(2-pyridyl)-phenylacetic acid (2.36g, 11.1 mmol), and EDC (2.13 g, 11.1 mmol). The reaction was stirredovernight whereupon it was poured into a rapidly-stirred mixture of 150mL each of EtOAc, 10% NaHCO₃, and brine. After stirring for 30 min, thelayers were separated and the aqueous layer was washed with fresh EtOAc(150 mL). The combined organic layers were washed with 10% Na₂CO₃, andbrine, then dried (MgSO₄), filtered, and concentrated. Columnchromatography (silica gel, 3:1 EtOAc:hexane) gave 2.275 g of the titlecompound: MS (ES+) (MH+) 257.2.

b) 3-(2-pyridyl)-phenylacetaldehyde

To a stirred solution of the compound of Example 22(a) (2.2 g, 8.6 mmol)in anhydrous THF (20 mL) at −78° C. was added a solution of lithiumaluminum hydride in THF (22 mL, 22.0 mmol). The reaction was stirred for2 h, then warmed to 0° C. and stirred 1 h, whereupon 4.2 g of KHSO₄ wasadded in small portions over 10 min, followed by 100 mL of water insmall portions. The reaction mixture was filtered to remove a whiteprecipitate and the filtrate was adjusted to pH 9 by the addition of 1 NNaOH, then extracted with Et₂O (3×100 mL). The combined organic layerswere washed with brine, then dried (Na₂SO₄), filtered, and concentratedto give 1.878 g of the title compound: MS (ES+) (MH+) 198.1.

c)1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[N^(α)-(tert-butoxycarbonylamino]-pyrrolidine

To a stirred solution of(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (672.3 mg, 3.6 mmol) inCH₂Cl₂ (15 mL) was added the compound of Example 22(b) (0.94 g, 4.3mmol). The reaction was stirred 2 h whereupon Na(OAc)₃BH (1.68 g, 7.9mmol) added. After stirring overnight, the reaction mixture was dilutedwith CHCl₃ (150 mL) and washed with H₂O, and brine, then dried (MgSO₄),filtered, and concentrated. Column chromatography (silica gel, 1:9MeOH:EtOAc) gave 467 mg of the title compound: MS (ES+) (MH+) 368.

d)1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

The compound of Example 22(c) (440 mg, 1.2 mmol) was dissolved in 4.0 NHCl in dioxane (20 mL) and stirred at room temperature for 30 min. Thesolution was concentrated to a white solid and dried under high vacuumfor 30 min. To a stirred solution of the residue in DMF (10 mL) wasadded N-methylmorpholine (400 uL, 3.6 mmol), HOBt (245.6 mg, 1.8 mmol),Boc-Leucine hydrate (449.1 mg, 1.8 mmol), and EDC (352.0 mg, 1.8 mmol).The reaction was stirred overnight whereupon it was partitioned between50 mL each of EtOAc, 10% Na₂CO₃, and brine. The aqueous layer was washedwith fresh EtOAc (50 mL), the combined organic layers were washed with10% Na₂CO₃ and brine, then dried (MgSO₄), filtered, and concentrated.Column chromatography (silica gel, 5:95 MeOH:EtOAc) gave 204 mg of thetitle compound: MS (ES+) (MH+) 481.4.

e)1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-L-leucinyl]amino]-pyrrolidinedihydrochloride

The compound of Example 22(d) (200 mg, 0.42 mmol) was dissolved in 4.0 NHCl in dioxane (25 mL) and stirred at room temperature for 1 h. Thesolution was concentrated to a white solid and dried under high vacuumfor 3 h to give the title compound: MS (ES+) (MH+) 381.4.

f)1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 22(e) (0.14 mmol) inDMF (2 mL) was added N-methylmorpholine (62 uL, 0.56 mmol), HOBt (31.8mg, 0.24 mmol), 2-naphthoic acid (37.6 mg, 0.22 mmol), and EDC (41.2 mg,0.22 mmol). The reaction was stirred overnight whereupon it waspartitioned between 50 mL each of EtOAc, 10% Na₂CO₃, and brine. Theaqueous layer was washed with fresh EtOAc (50 mL), the combined organiclayers were washed with 10% Na₂CO₃ and brine, then dried (MgSO₄),filtered, and concentrated. Column chromatography (silica gel, 5:95MeOH:EtOAc) gave 40.1 mg of the title compound: MS (ES+) (MH+) 535.4.

Example 23 Preparation of1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 22(f), except using2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+)(MH+) 536.4.

Example 24 Preparation of1-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[N^(α)-(3-isoquinolinecarbonyl-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 22(f), except using3-isoquinolinecarboxylic acid, the title compound was prepared: MS (ES+)(MH+) 536.4.

Example 25 Preparation of1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea)1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[N^(α)-(tert-butoxycarbonylamino]-pyrrolidine

Following the procedure of Example 22(c), except substituting(3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine, the title compound wasprepared: MS (ES+) (MH+) 368.4.

b)1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 22(d), except substituting thecompound of Example 25(a), the title compound was prepared: MS (ES+)(MH+) 481.4.

c)1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)-L-leucinyl]amino]-pyrrolidinedihydrochloride

Following the procedure of Example 22(e), except substituting thecompound of Example 25(b), the title compound was prepared: MS (ES+)(MH+) 381.4.

d)1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 22 (f), except substituting thecompound of Example 25 (c), the title compound was prepared: MS (ES+)(MH+) 535.3.

Example 26 Preparation of1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 25(d), except using3-isoquinolinecarboxylic acid, the title compound was prepared: MS (ES+)(MH+) 536.3.

Example 27 Preparation of1-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N^(α)(-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 25(d), except using2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+)(MH+) 536.3.

Example 28 Preparation of1-(1-adamantanecarbonyl)-(3R)-[[N^(α)-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]-pyrrolidinea)1-(1-adamantanecarbonyl)-(3R)-[[N^(α)-(tert-butyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of(3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (1.87 g, 10.0 mmol) inCH₂Cl₂ (30 mL) at 0° C. was added N-methylmorpholine (1.65 mL, 15.0mmol) and 1-adamantylcarbonyl chloride (2.99 g, 15.0 mmol). The reactionwas stirred overnight, gradually warming to room temperature, whereuponit was diluted with 200 mL of CHCl₃ , washed with 5% NaHCO₃, H₂O, 1NHCl, H₂O, and brine, then dried (MgSO₄), filtered, and concentrated togive 4.66 g of the title compound: MS (ES+) (MH+) 349.4.

b) 1-(1-adamantanecarbonyl)-(3R)-aminopyrrolidine hydrochloride

The compound of Example 28 (a) (4.6 g) was dissolved in 4.0 N HCl indioxane (100 mL) and stirred at room temperature for 1 h. The solutionwas concentrated to a white solid and dried under high vacuum for 2 h togive the title compound: MS (ES+) (MH+) 249.1.

c)1-(1-adamantanecarbonyl)-(3R)-[[N^(α)-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 28(b) (143.2 mg, 0.50mmol) in DMF (2 mL) was added N-methylmorpholine (83 uL, 0.75 mmol),HOBt (101.5 mg, 0.75 mmol), 4-Inoc-Leucine (201.5 mg, 0.76 mmol), andEDC (146.0 mg, 0.76 mmol). The reaction was stirred overnight whereuponit was partitioned between 50 mL each of EtOAc, 10% Na₂CO₃, and brine.The aqueous layer was washed with fresh EtOAc (50 mL), the combinedorganic layers were washed with 10% Na₂CO₃ and brine, then dried(MgSO₄), filtered, and concentrated. Column chromatography (silica gel,2:98 MeOH:EtOAc) gave 109.0 mg of the title compound: MS (ES+) (MH+)497.5.

Example 29 Preparation of1-(1-adamantanecarbonyl)-(3S)-[[N^(α)-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]-pyrrolidinea)1-(1-adamantanecarbonyl)-(3S)-[[N^(α)-(tert-butyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 28(a), except substituting(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, the title compound wasprepared: MS (ES+) (MH+) 349.5.

b) 1-(1-adamantanecarbonyl)-(3S)-aminopyrrolidine hydrochloride

Following the procedure of Example 28(b), except substituting thecompound of Example 29 (a), the title compound was prepared: MS (ES+)(MH+) 249.1.

c)1-(1-adamantanecarbonyl)-(3S)-[[N^(α)-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 28(c), except substituting thecompound of Example 29(b), the title compound was prepared: MS (ES+)(MH+) 497.4.

Example 30 Preparation of(3R)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinea)(3R)-[[N^(α)-(tert-butoxycarbonyl)amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

To a stirred solution of(3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (2 g, 10.7 mmol) inCH₂Cl₂ (200 mL) was added N-CBZ-Leucinal (3.2 g, 12.9 mmol). Thereaction was stirred 2 h whereupon Na(OAc)₃BH (3.4 g, 16.1 mmol) wasadded. After stirring overnight, the reaction mixture was diluted withCHCl₃ (150 mL) and washed with 5% NaHCO₃ and brine, then dried (MgSO₄),filtered, and concentrated. Column chromatography (silica gel, 3:97MeOH:CH₂Cl₂) gave 3.4 g of the title compound: MS (ES+) (MH+) 420.

b)(3R)-amino-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinedihydrochloride

The compound of Example 30 (a) (3.4 g) was dissolved in 4.0 N HCl indioxane (50 mL) and stirred at room temperature for 1 h. The solutionwas concentrated in vacuo and dried under high vacuum to give 3.37 g ofthe title compound: MS (ES+) (MH+) 320.

c)(3R)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

To a stirred solution of the compound of Example 30(b) (2.36 g, 6.0mmol) in DMF (25 mL) was added N-methylmorpholine (2.0 mL, 18.2 mmol),HOBt (1.22 g, 9.0 mmol), Boc-Leucine hydrate (2.25 g, 9.0 mmol), and EDC(1.73 g, 9.0 mmol). The reaction was stirred for 3 h whereupon it waspartitioned between 150 mL each of EtOAc, 10% Na₂CO₃, and brine. Theaqueous layer was washed with fresh EtOAc (150 mL), the combined organiclayers were washed with 10% Na₂CO₃ and brine, then dried (MgSO₄),filtered, and concentrated. Column chromatography (silica gel, 2:1EtOAc:hexane) gave 2.78 g of the title compound: MS (ES+) (MH+) 533.6.

d)(3R)-[[N^(α)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinedihydrochloride

The compound of Example 30(c) (2.7 g) was dissolved in 4.0 N HCl indioxane (100 mL) and stirred at room temperature for 1 h. The solutionwas concentrated in vacuo and dried azeotropically with toluene toafford a tan solid and stored under high vacuum overnight to give 2.45 gof the title compound: MS (ES+) (MH+) 433.3.

e)(3R)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

To a stirred solution of the compound of Example 30(d) (101.4 mg, 0.2mmol) in DMF (1 mL) was added N-methylmorpholine (66 uL, 0.6 mmol), HOBt(42.2 mg, 0.3 mmol), benzo[b]thiophene-2-carboxylic acid (53.3 mg, 0.3mmol), and EDC (57.8 mg, 0.3 mmol). The reaction was stirred overnightwhereupon it was partitioned between 50 mL each of EtOAc, 10% Na₂CO₃,and brine. The aqueous layer was washed with fresh EtOAc (50 mL), thecombined organic layers were washed with 10% Na₂CO₃ and brine, thendried (MgSO₄), filtered, and concentrated. Column chromatography (silicagel, 3:1 EtOAc:hexane) gave 80.4 mg of the title compound: MS (ES+)(MH+) 593.4.

Example 31 Preparation of(3R)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substituting3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+)(MH+) 597.4.

Example 32 Preparation of(3R)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-1-(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substitutingbenzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 577.2.

Example 33 Preparation of(3R)-[[N^(α)-(benzothiazole-6-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substitutingbenzothiazole-6-carboxylic acid, the title compound was prepared: MS(ES+) (MH+) 594.4.

Example 34 Preparation of(3R)-[[N^(α)-(indole-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substitutingindole-2-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 576.3.

Example 35 Preparation of(3R)-[[N^(α)-(4-fluorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substituting4-fluorobenzoic acid, the title compound was prepared: MS (ES+) (MH+)555.3.

Example 36 Preparation of(3R)-[[N^(α)-(4-methoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substitutingp-4-methoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+)567.4.

Example 37 Preparation of(3R)-[[N^(α)-(3,4-dichlorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 1(e), except substituting3,4-dichlorobenzoic acid, the title compound was prepared: MS (ES+)(MH+) 605.2.

Example 38 Preparation of(3R)-[[N^(α)-(thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substitutingthiophene-3-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 543.4.

Example 39 Preparation of(3R)-[[N^(α)-(4-biphenylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

To a stirred solution of the compound of Example 30(d) (102.3 mg, 0.2mmol) in CH₂Cl₂ (1 mL) at 0° C. was added N-methylmorpholine (66 uL, 0.6mmol) and 4-biphenylcarbonyl chloride (65.2 mg, 0.3 mmol). The reactionwas stirred overnight whereupon it was diluted with CHCl₃ and washedwith 10% Na₂CO₃ and brine, then dried (MgSO₄), filtered, andconcentrated. Column chromatography (silica gel, 3:1 EtOAc:hexane) gave55.1 mg of the title compound: MS (ES+) (MH+) 613.5.

Example 40 Preparation of(3R)-[[N^(α)-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substituting5-methoxybenzofuran-2-carboxylic acid, the title compound was prepared:MS (ES+) (MH+) 607.4.

Example 41 Preparation of(3R)-[[N^(α)-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substituting5-chlorobenzofuran-2-carboxylic acid, the title compound was prepared:MS (ES+) (MH+) 611.4.

Example 42 Preparation of(3R)-[[N^(α)-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substituting7-methoxybenzofuran-2-carboxylic acid, the title compound was prepared:MS (ES+) (MH+) 607.4.

Example 43 Preparation of(3R)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substituting3-chlorobenzo[b]thiophene-2-carboxylic acid, the title compound wasprepared: MS (ES+) (MH+) 627.3.

Example 44 Preparation of(3R)-[[N^(α)-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substituting3-(2-pyridyl)benzoic acid, the title compound was prepared: MS (ES+)(MH+) 614.4.

Example 45 Preparation of(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinea)(3S)-[[N^(α)-(tert-butoxycarbonyl)amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(a), except substituting(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, the title compound wasprepared: MS (ES+) (MH+) 420.

b)(3S)-amino-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinedihydrochloride

Following the procedure of Example 30(b), except substituting thecompound of Example 45(a), the title compound was prepared: MS (ES+)(MH+) 320.

c)(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(c), except substituting thecompound of Example 45(b), the title compound was prepared: MS (ES+)(MH+) 533.5.

d)(3S)-[[N^(α)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidinedihydrochloride

Following the procedure of Example 30(d), except substituting thecompound of Example 45(c), the title compound was prepared: MS (ES+)(MH+) 433.3.

e)(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 30(e), except substituting thecompound of Example 45(d), the title compound was prepared: MS (ES+)(MH+) 593.4.

Example 46 Preparation of(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substituting3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+)(MH+) 597.5.

Example 47 Preparation of(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substitutingbenzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 577.4.

Example 48 Preparation of(3S)-[[N^(α)-(benzothiazole-6-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substitutingbenzothiazole-6-carboxylic acid, the title compound was prepared: MS(ES+) (MH+) 594.4.

Example 49 Preparation of(3S)-[[N^(α)-(indole-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substitutingindole-2-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 576.4.

Example 50 Preparation of(3S)-[[N^(α)-(4-fluorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substituting4-fluorobenzoic acid, the title compound was prepared: MS (ES+) (MH+)555.3.

Example 51 Preparation of(3S)-[[N^(α)-(4-methoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substitutingp-4-methoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+)567.3.

Example 52 Preparation of(3S)-[[N^(α)-(3,4-dichlorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substituting3,4-dichlorobenzoic acid, the title compound was prepared: MS (ES+)(MH+) 605.2.

Example 53 Preparation of(3S)-[[N^(α)-(thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substitutingthiophene-3-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 543.2.

Example 54 Preparation of(3S)-[[N^(α)-(4-biphenylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 39, except substituting the compoundof Example 45(e), the title compound was prepared: MS (ES+) (MH+) 613.4.

Example 55 Preparation of(3S)-[[N^(α)-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substituting5-methoxybenzofuran-2-carboxylic acid, the title compound was prepared:MS (ES+) (MH+) 607.4.

Example 56 Preparation of(3S)-[[N^(α)-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substituting5-chlorobenzofuran-2-carboxylic acid, the title compound was prepared:MS (ES+) (MH+) 611.4.

Example 57 Preparation of(3S)-[[N^(α)-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substituting7-methoxybenzofuran-2-carboxylic acid, the title compound was prepared:MS (ES+) (MH+) 607.4.

Example 58 Preparation of(3S)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substituting3-chlorobenzo[b]thiophene-2-carboxylic acid, the title compound wasprepared: MS (ES+) (MH+) 627.2.

Example 59 Preparation of(3S)-[[N^(α)-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine

Following the procedure of Example 45(e), except substituting3-(2-pyridyl)benzoic acid, the title compound was prepared: MS (ES+)(MH+) 614.4.

Example 60 Preparation of1-(4-phenyl)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidinea)1-(2,2,2-trichloroethylcarbonyl)-(3S)-[[N^(α)-(tert-butoxycarbonyl)amino]-pyrrolidine

To a stirred solution of(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (10 g, 53.7 mmol) inCH₂Cl₂ (150 mL) at 0° C. was added N-methylmorpholine (6.50 mL, 59.1mmol), and 2,2,2-trichloroethyl chloroformate (8.20 mL, 59.6 mmol).After stirring overnight, gradually warming to room temperature, thereaction mixture was concentrated to 1/2 original volume, diluted withCHCl₃ (250 mL), and washed with 5% NaHCO₃, H₂O, 1N HCl, H₂O, and brine,then dried (MgSO₄), filtered, and concentrated to give 23.98 g of thetitle compound: ¹H-NMR (400 MHz, CDCl₃): d (ppm) 4.74 (s, 2H); 4.66 (brm, 1H); 4.25 (br m, 1H); 3.72 (m, 1H); 3.56 (m, 2H); 3.33 (m, 1H); 2.19(m, 1H); 1.87 (m, 1H); 1.45 (s, 9H).

b)1-(2,2,2-trichloroethylcarbonyl)-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

The compound of Example 60(a) (23.9 g) was dissolved in 4.0 N HCl indioxane (200 mL) and stirred at room temperature for 1 h. The solutionwas concentrated to a white solid and stored under high vacuum for 30min. To a stirred solution of the residue in DMF (200 mL) was addedN-methylmorpholine (8.90 mL, 80.9 mmol), HOBt (10.88 g, 80.5 mmol),Boc-Leucine hydrate (20.09 g, 80.6 mmol), and EDC (15.44 g, 80.6 mmol).The reaction was stirred overnight whereupon it was partitioned betweenEtOAc (300 mL), 10% Na₂CO₃ (150 mL), and brine (150 mL). The aqueouslayer was washed with fresh EtOAc (100 mL), the combined organic layerswere washed with 1N HCl, H₂O, 10% Na₂CO₃, H₂O, and brine, then dried(MgSO₄), filtered, and concentrated to give 27.88 g of the titlecompound: MS (ES+) (MH+) 474.1.

c) (3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 60(b) (27.7 g) in THF(200 mL) was added a solution of 1N NH₄OAc (pH 7-7.5, 40 mL), followedby Zn powder (25.06 g). The reaction was stirred for 3 h at roomtemperature whereupon the slurry was filtered through a pad of Celite,followed by several CHCl₃ washes. The combined filtrates wereconcentrated to remove THF, diluted with additional CHCl₃ (300 mL) andwashed with 10% Na₂CO₃ and brine, then dried (MgSO₄), filtered, andconcentrated to give 16.34 g of the title compound: MS (ES+) (MH+)300.2.

d)1-(4-phenyl)benzyl-(3S)-[[N^(α)-t-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 60(c) (1.51 g, 5.0mmol) in CH₂Cl₂ (10 mL) was added 4,4′-biphenylcarboxaldehyde (1.09 g,6.0 mmol). The reaction was stirred 2 h whereupon Na(OAc)₃ (2.34 g, 11.0mmol) was added. After stirring overnight, the reaction mixture wasdiluted with CHCl₃ (100 mL) and washed with 5% NaHCO₃ and brine, thendried (MgSO₄), filtered, and concentrated. Column chromatography (silicagel, 2:1 EtOAc:hexane to 3:1 EtOAc:hexane) gave 1.68 g of the titlecompound: MS (ES+) (MH+) 466.4.

Example 61 Preparation of1-(4-phenyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea) 1-(4-phenyl)benzyl-(3S)-[[N^(α)-L-leucinyl]amino]-pyrrolidinedihydrochloride

The compound of Example 60(d) (1.57 g, 3.4 mmol) was dissolved in 4.0 NHCl in dioxane (25 mL) and stirred at room temperature for 1 h. Thesolution was concentrated to a white solid and dried under high vacuumfor 30 min to give the title compound: MS (ES+) (MH+) 366.4.

b)1-(4-phenyl)benzyl-(3S)-[[N-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 61(a) (132.9 mg, 0.30mmol) in DMF (1 mL) was added N-methylmorpholine (100 uL, 0.91 mmol),HOBt (62.0 mg, 0.46 mmol), 2-naphthoic acid (78.4 mg, 0.46 mmol), andEDC (87.3 mg, 0.46 mmol). The reaction was stirred overnight whereuponit was partitioned between 50 mL each of EtOAc, 10% Na₂CO₃, and brine.The aqueous layer was washed with fresh EtOAc (50 mL), the combinedorganic layers were washed with 10% Na₂CO₃ and brine, then dried(MgSO₄), filtered, and concentrated. Column chromatography (silica gel,2:1 EtOAc:hexane) gave 102.8 mg of the title compound: MS (ES+) (MH+)520.3.

Example 62 Preparation of1-(4-phenyl)benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 61(b), except substituting2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+)(MH+) 521.3.

Example 63 Preparation of1-(4-phenyl)benzyl-(3S)-[[N^(α)-(3-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 61(b), except substituting3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+)(MH+) 530.3.

Example 64 Preparation of1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 61(b), except substitutingbenzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 510.3.

Example 65 Preparation of1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 61(b), except substitutingbenzo[b]thiophene-2-carboxylic acid, the title compound was prepared: MS(ES+) (MH+) 526.4.

Example 66 Preparation of1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred suspension of the compound of Example 61(a) (132.9 mg, 0.30mmol) in CH₂Cl₂ (2 mL) at 0° C. was added N-methylmorpholine (132 uL,1.20 mmol), and benzyl chloroformate (53 uL, 0.36 mmol). The reactionwas stirred overnight, gradually warming to room temperature, whereuponit was diluted with CHCl₃ (100 mL) and washed with 10% Na₂CO₃ and brine,then dried (MgSO₄), filtered, and concentrated. Column chromatography(silica gel, EtOAc) gave 94.0 mg of the title compound: MS (ES+) (MH+)500.3.

Example 67 Preparation of1-(2-phenyl)ethyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 60(d), except substitutingphenylacetaldehyde, the title compound was prepared: MS (ES+) (MH+)404.4.

Example 68 Preparation of1-(2-phenyl)ethyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea) 1-(2-phenyl)ethyl-(3S)-[[N^(α)-L-leucinyl]amino]-pyrrolidinedihydrochloride

The compound of Example 67 (1.13 g, 2.8 mmol) was dissolved in 4.0 N HClin dioxane (25 mL) and stirred at room temperature for 1 h. The solutionwas concentrated to a white solid and dried under high vacuum for 30 minto give the title compound: MS (ES+) (MH+) 304.3.

b)1-(2-phenyl)ethyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 61(b), except substituting thecompound of Example 68(a), the title compound was prepared: MS (ES+)(MH+) 458.3.

Example 69 Preparation of1-(2-phenyl)ethyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 68(b), except substituting2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+)(MH+) 459.5.

Example 70 Preparation of1-(2-phenyl)ethyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 68(b), except substitutingbenzo[b]thiophene-2-carboxylic acid, the title compound was prepared: MS(ES+) (MH+) 464.3.

Example 71 Preparation of1-(2-phenyl)ethyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 68(b), except substitutingbenzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 448.3.

Example 72 Preparation of1-(2-phenyl)ethyl-(3S)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 68(b), except substituting3-chlorobenzo[b]thiophene -2-carboxylic acid, the title compound wasprepared: MS (ES+) (MH+) 498.1.

Example 73 Preparation of1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 60(d), except substituting4-phenoxybenzaldehyde, the title compound was prepared: MS (ES+) (MH+)482.4.

Example 74 Preparation of1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea) 1-(4-phenoxy)benzyl-(3S)-[[N^(α)-L-leucinyl]amino]-pyrrolidinedihydrochloride

The compound of Example 73 (1.52 g, 3.2 mmol) was dissolved in 4.0 N HClin dioxane (25 mL) and stirred at room temperature for 1 h. The solutionwas concentrated to a white solid and dried under high vacuum for 30 minto give the title compound: MS (ES+) (MH+) 382.4.

b)1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 61(b), except substituting thecompound of Example 74(a), the title compound was prepared: MS (ES+)(MH+) 536.3.

Example 75 Preparation of1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 74(b), except substituting2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+)(MH+) 537.3.

Example 76 Preparation of1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 74(b), except substituting3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+)(MH+) 546.3.

Example 77 Preparation of1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 74(b), except substitutingbenzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+)(MH+) 526.4.

Example 78 Preparation of1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 74(b), except substitutingbenzo[b]thiophene-2-carboxylic acid, the title compound was prepared: MS(ES+) (MH+) 542.3.

Example 79 Preparation of1-(4-fluoro)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 60(d), except substituting4-fluorobenzaldehyde, the title compound was prepared: MS (ES+) (MH+)408.3.

Example 80 Preparation of1-(4-fluoro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea) 1-(4-fluoro)benzyl-(3S)-[[N^(α)-L-leucinyl]amino]-pyrrolidinedihydrochloride

The compound of Example 79 (508 mg, 1.25 mmol) was dissolved in 4.0 NHCl in dioxane (25 mL) and stirred at room temperature for 1 h. Thesolution was concentrated to a white solid and dried under high vacuumfor 30 min to give the title compound: MS (ES+) (MH+) 308.3.

b)1-(4-fluoro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 61(b), except substituting thecompound of Example 80(a), the title compound was prepared: MS (ES+)(MH+) 462.3.

Example 81 Preparation of1-(4-fluoro)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 80(b), except substitutingbenzo[b]thiophene-2-carboxylic acid, the title compound was prepared: MS(ES+) (MH+) 468.3.

Example 82 Preparation of1-(4-cyano)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 60(d), except substituting4-cyanobenzaldehyde, the title compound was prepared: MS (ES+) (MH+)415.4.

Example 83 Preparation of1-(4-cyano)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea) 1-(4-cyano)benzyl-(3S)-[[N^(α)-L-leucinyl]amino]-pyrrolidinedihydrochloride

The compound of Example 82 (512 mg, 1.23 mmol) was dissolved in 4.0 NHCl in dioxane (25 mL) and stirred at room temperature for 1 h. Thesolution was concentrated to a white solid and dried under high vacuumfor 30 min to give the title compound: MS (ES+) (MH+) 315.4.

b)1-(4-cyano)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 61(b), except substituting thecompound of Example 83(a), the title compound was prepared: MS (ES+)(MH+) 469.5.

Example 84 Preparation of1-benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidinea) 1-benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)amino]-pyrrolidine

To a stirred solution of(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (10 g, 53.7 mmol) inCH₂Cl₂ (125 mL) was added benzaldehyde (6.6 mL, 64.9 mmol). The reactionwas stirred 2 h whereupon Na(OAc)₃ (25.05 g, 118.2 mmol) was added.After stirring overnight, small aliquots of 5% NaHCO₃ were added untilfoaming had ceased. The reaction mixture was diluted with CHCl₃ (150 mL)and washed with 5% NaHCO₃ and brine, then dried (MgSO₄), filtered, andconcentrated. Column chromatography (silica gel, 1:1 EtOAc:hexane) gave11.5 g of the title compound: MS (ES+) (MH+) 277.2.

b)1-benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

The compound of Example 84(a) (11.0 g, 39.8 mmol) was dissolved in 4.0 NHCl in dioxane (300 mL) and stirred at room temperature for 1 h. Thesolution was concentrated to a white solid and dried under high vacuum.To a stirred solution of the residue in DMF (100 mL) was addedN-methylmorpholine (13.1 mL, 119.1 mmol), HOBt (8.07 g, 59.7 mmol),Boc-Leucine hydrate (14.89 g, 59.7 mmol), and EDC (11.44 g, 59.7 mmol).The reaction was stirred overnight whereupon it was diluted with EtOAc(500 mL), and washed with 1:1 10% Na₂CO₃:brine (300 mL). The aqueouslayer was washed with fresh EtOAc (150 mL), the combined organic layerswere washed with 10% Na₂CO₃ and brine, then dried (MgSO₄), filtered, andconcentrated. Column chromatography (silica gel, 1:2 EtOAc:hexane to 1:1EtOAc:hexane) gave 13.5 g of the title compound: MS (ES+) (MH+) 390.4.

c) 1-benzyl-(3S)-[[N^(α)-L-leucinyl]amino]-pyrrolidine dihydrochloride

The compound of Example 84(b) (11.6 g, 29.8 mmol) was dissolved in 4.0 NHCl in dioxane (300 mL) and stirred at room temperature for 1 h. Thesolution was concentrated to a white solid and dried under high vacuumto give the title compound: MS (ES+) (MH+) 290.4.

d)1-benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 84 (c) (109.2 mg, 0.30mmol) in DMF (1 mL) was added N-methylmorpholine (100 uL, 0.91 mmol),HOBt (61.6 mg, 0.46 mmol), benzo[b]thiophene-2-carboxylic acid (80.8 mg,0.45 mmol), and EDC (86.6 mg, 0.45 mmol). The reaction was stirredovernight whereupon it was partitioned between 50 mL each of EtOAc, 10%Na₂CO₃, and brine. The aqueous layer was washed with fresh EtOAc (50mL), the combined organic layers were washed with 10% Na₂CO₃ and brine,then dried (MgSO₄), filtered, and concentrated. Column chromatography(silica gel, 4:1 EtOAc:hexane) gave 85.0 mg of the title compound: MS(ES+) (MH+) 450.0.

Example 85 Preparation of1-benzyl-(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 84(d), except substituting3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+)(MH+) 454.4.

Example 86 Preparation1-benzyl-(3S)-[[N^(α)-(3-(2-dimethylaminoethoxy)-4-methoxybenzoyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 84(d), except substituting3-(2-dimethylaminoethoxy)-4-methoxybenzoic acid, the title compound wasprepared: MS (ES+) (MH+) 511.2.

Example 87 Preparation of1-(4-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea)1-benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 84(c) (7.25 g, 20.0mmol) in DMF (50 mL) was added N-methylmorpholine (6.60 mL, 60.0 mmol),HOBt (4.05 g, 30.0 mmol), 2-naphthoic acid (5.17 g, 30.0 mmol), and EDC(5.76 g, 30.1 mmol). The reaction was stirred overnight whereupon it waspartitioned between EtOAc (300 mL), 10% Na₂CO₃ (150 mL), and brine (150mL). The aqueous layer was washed with fresh EtOAc (150 mL), thecombined organic layers were washed with 10% Na₂CO₃ and brine, thendried (MgSO₄), filtered, and concentrated. Column chromatography (silicagel, 3:1 EtOAc:hexane to EtOAc) gave 5.7 g of the title compound: MS(ES+) (MH+) 444.0.

b) (3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred suspension of the compound of Example 87(a) (2.22 g, 5.00mmol) in anhydrous dichloroethane (10 mL) at 0° C., in an oven-driedflask under an Argon atmosphere, was added a solution of 1-chloroethylchloroformate (600 uL, 5.56 mmol) in dichloroethane, drop-wise over 10min. After stirring at 0° C. for 15 min, the reaction was heated toreflux for 1.5 h, cooled to room temperature, and concentrated. Theresidue was dissolved in anhydrous MeOH (10 mL) and heated to refluxovernight, The reaction was cooled to room temperature, whereupon it wasconcentrated, dissolved in H₂O, and basified to pH 9-9.5 by the additionof solid Na₂CO₃. The aqueous solution was extracted with CHCl₃ (2×100mL), the combined organic layers were washed with brine, then dried(MgSO₄), filtered, and concentrated. Column chromatography (silica gel,10:90 MeOH:CHCl₃ to 10:90:0.1 MeOH:CHCl₃:NH₄OH) gave 0.82 g of the titlecompound: MS (ES+) (MH+) 354.3.

c)1-(4-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 87(b) (106.5 mg, 0.30mmol) in CH₂Cl₂ (1 mL) was added 4-nitrobenzaldehyde (55.5 mg, 0.37mmol). The reaction was stirred 1.5 h whereupon Na(OAc)₃ (141.3 mg, 0.67mmol) added. After stirring overnight, the reaction mixture was dilutedwith CHCl₃ (100 mL) and washed with 5% NaHCO₃ and brine, then dried(MgSO₄), filtered, and concentrated. Column chromatography (silica gel,EtOAc) gave 88.0 mg of the title compound: MS (ES+) (MH+) 489.3.

Example 88 Preparation of1-(4-(N,N-dimethylamino)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substituting4-(N,N-dimethylamino)benzaldehyde, the title compound was prepared: MS(ES+) (MH+) 487.1.

Example 89 Preparation of1-(4-methoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substitutingp-anisaldehyde, the title compound was prepared: MS (ES+) (MH+) 474.4.

Example 90 Preparation of1-(4-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substituting4-pyridinecarboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 445.4.

Example 91 Preparation of1-(4-carboxymethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substitutingmethyl-4-formylbenzoate, the title compound was prepared: MS (ES+) (MH+)502.3.

Example 92 Preparation of1-(3,4-methylenedioxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substituting piperonal,the title compound was prepared: MS (ES+) (MH+) 488.2.

Example 93 Preparation of1-(2-naphthyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substituting2-naphthaldehyde, the title compound was prepared: MS (ES+) (MH+) 494.2.

Example 94 Preparation of1-(3-indolyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substitutingindole-3-carboxaldehyde, the title compound was prepared: MS (ES+) (MH+)483.4.

Example 95 Preparation of1-(2-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87c), except substitutingquinoline-2-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 495.4.

Example 96 Preparation of1-(3-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substitutingquinoline-3-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 495.3.

Example 97 Preparation of1-(1-naphthyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substituting1-naphthaldehyde, the title compound was prepared: MS (ES+) (MH+) 494.3.

Example 98 Preparation of1-(4-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substitutingquinoline-4-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 495.3.

Example 99 Preparation1-(3-pyrrolyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substitutingpyrrole-2-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 433.3.

Example 100 Preparation of1-(3-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substitutingpyridine-3-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 445.2.

Example 101 Preparation of1-(2-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substitutingpyridine-2-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 445.1.

Example 102 Preparation of1-(3-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 87(c), except substituting3-nitrobenzaldehyde, the title compound was prepared: MS (ES+) (MH+)489.3.

Example 103 Preparation of1-(4-acetamido)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidinea)1-(2,2,2-trichloroethyl)carbonyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)amino]-pyrrolidine

To a stirred solution of(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (10 g, 53.7 mmol) inCH₂Cl₂ (150 mL) at 0° C. was added N-methylmorpholine (6.50 mL, 59.1mmol), and 2,2,2-trichloroethyl chloroformate (8.20 mL, 59.6 mmol).After stirring overnight, gradually warming to room temperature, thereaction mixture was diluted with CHCl₃ (250 mL) and washed with 5%NaHCO₃, H₂O, 1N HCl, H₂O, and brine, then dried (MgSO₄), filtered, andconcentrated to give 19.96 g of the title compound: ¹H-NMR (400 MHz,CDCl₃): d (ppm) 4.74 (s, 2H); 4.66 (br m, 1H); 4.25 (br m, 1H); 3.72 (m,1H); 3.56 (m, 2H); 3.33 (m, 1H); 2.19 (m, 1H); 1.87 (m, 1H); 1.45 (s,9H).

b)1-(2,2,2-trichloroethyl)carbonyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine

The compound of Example 103(a) (19.9 g) was dissolved in 4.0 N HCl indioxane (400 mL) and stirred at room temperature for 1 h. The solutionwas concentrated to a white solid and stored under high vacuum. To astirred solution of the residue in DMF (200 mL) was addedN-methylmorpholine (8.90 mL, 80.9 mmol), HOBt (10.88 g, 80.5 mmol),Boc-Leucine hydrate (20.10 g, 80.6 mmol), and EDC (15.45 g, 80.7 mmol).The reaction was stirred overnight whereupon it was concentrated toremove most of the DMF, then diluted with EtOAc (300 mL), and washedwith brine (150 mL). The aqueous layer was washed with fresh EtOAc (100mL), the combined organic layers were washed with 1N HCl, H₂O, 10%Na₂CO₃, H₂O, and brine, then dried (MgSO₄), filtered, and concentratedto give 24.64 g of the title compound: ¹H-NMR (400 MHz, CDCl₃): d (ppm)6.55 (br m, 1H); 4.88 (m, 1H); 4.76 (s, 2H); 4.48 (m, 1H); 4.03 (m, 1H);3.75 (m, 1H); 3.58 (m, 2H); 3.33 (m, 1H); 2.19 (m, 1H); 1.88 (m, 1H);1.64 (m, 2H); 1.49 (m, 1H); 1.44 (s, 9H); 0.93 (m, 6H).

c)1-(2,2,2-trichloroethyl)carbonyl-(3S)-[[N^(α)-L-leucinyl]amino]-pyrrolidinehydrochloride

The compound of Example 103 (b) (24.5 g) was dissolved in 4.0 N HCl indioxane (500 mL) and stirred at room temperature for 1 h. The solutionwas concentrated to a white solid and dried under high vacuum to givethe title compound: MS (ES+) (MH+) 375.

d)1-(2,2,2-trichloroethyl)carbonyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 103(c) (10.28 g, 25.0mmol) in DMF (75 mL) was added N-methylmorpholine (4.2 mL, 38.2 mmol),HOBt (5.07 g, 37.5 mmol), 2-naphthoic acid (6.46 g, 37.5 mmol), and EDC(7.18 g, 37.5 mmol). The reaction was stirred overnight whereupon it wasconcentrated to remove most of the DMF, then partitioned between EtOAc(300 mL), 1N HCl (150 mL), and brine (150 mL). The aqueous layer waswashed with fresh EtOAc (150 mL), the combined organic layers werewashed with 1N HCl, H₂O, 10% Na₂CO₃, H₂O, and brine, then dried (MgSO₄),filtered, and concentrated. Column chromatography (silica gel, 1:2EtOAc:hexane to 1:1 EtOAc:hexane) gave 9.74 g of the title compound: MS(ES+) (MH+) 528.1.

e) (3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 103(d) (9.65 g) in THF(75 mL) was added a solution of 1N NH₄OAc (pH 7-7.5, 15 mL), followed byZn powder (9.53 g). The reaction was stirred for 5 h at room temperaturewhereupon fresh Zn (4 g) was added and the reaction was stirredovernight. The slurry was filtered through a pad of Celite, followed byseveral THF washes. The combined filtrates were concentrated to removeTHF, diluted with CHCl₃ (300 mL), washed with 10% Na₂CO₃ and brine, thendried (MgSO₄), filtered, and concentrated. Column chromatography (silicagel, 10:90 MeOH:CHCl₃ to 10:90:0.25 MeOH:CHCl₃:NH₄OH) gave 5.71 g of thetitle compound: MS (ES+) (MH+) 354.2.

f)1-(4-acetamido)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

To a stirred solution of the compound of Example 103(e) (106.5 mg, 0.3mmol) in CH₂Cl₂ (1 mL) was added 4-acetamidobenzaldehyde (59.7 mg, 0.37mmol). The reaction was stirred 2 h whereupon Na(OAc)₃ (140.0 mg, 0.66mmol) was added. After stirring overnight, the reaction mixture wasdiluted with CHCl₃ (100 mL) and washed with 5% NaHCO₃ and brine, thendried (MgSO₄), filtered, and concentrated. Column chromatography (silicagel, 5:95 MeOH:EtOAc) gave 105.1 mg of the title compound: MS (ES+)(MH+) 501.4.

Example 104 Preparation of1-(3-cyano)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting3-cyanobenzaldehyde, the title compound was prepared: MS (ES+) (MH+)469.2.

Example 105 Preparation of1-(3-fluoro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting3-fluorobenzaldehyde, the title compound was prepared: MS (ES+) (MH+)462.3.

Example 106 Preparation of1-(3-phenoxy)benzyl-(3S)-[[N^(α)-(2naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting3-phenoxybenzaldehyde, the title compound was prepared: MS (ES+) (MH+)536.3.

Example 107 Preparation of1-(4-chloro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting4-chlorobenzaldehyde, the title compound was prepared: MS (ES+) (MH+)478.3.

Example 108 Preparation of1-(4-trifluoromethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting4-(trifluoromethyl)benzaldehyde, the title compound was prepared: MS(ES+) (MH+) 512.3.

Example 109 Preparation of1-(3-trifluoromethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting3-(trifluoromethyl)benzaldehyde, the title compound was prepared: MS(ES+) (MH+) 512.2.

Example 110 Preparation of1-(4-(3-(N,N-dimethylamino)propoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting4-(3-dimethylaminopropoxy)benzaldehyde, the title compound was prepared:MS (ES+) (MH+) 545.2.

Example 111 Preparation of1-(4-(isopropyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting4-isopropylbenzaldehyde, the title compound was prepared: MS (ES+) (MH+)486.4.

Example 112 Preparation of1-(2-benzofuranyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substitutingbenzofuran-2-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 484.2.

Example 113 Preparation of1-(2-(3-methylbenzo[b]thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting3-methylbenzo[b]thiophene-2-carboxaldehyde, the title compound wasprepared: MS (ES+) (MH+) 514.2.

Example 114 Preparation of1-(2-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substitutingfuran-2-carboxaldehyde, the title compound was prepared: MS (ES+) (MH+)434.1.

Example 115 Preparation of1-(3-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substitutingfuran-3-carboxaldehyde, the title compound was prepared: MS (ES+) (MH+)434.3.

Example 116 Preparation of SB1-(2-thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substitutingthiophene-3-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 450.3.

Example 117 Preparation of1-(2-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting2-nitrobenzaldehyde, the title compound was prepared: MS (ES+) (MH+)489.3.

Example 118 Preparation of1-(3-thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substitutingthiophene-2-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 450.2.

Example 119 Preparation of1-(3,4-diomethoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting3,4-dimethoxybenzaldehyde, the title compound was prepared: MS (ES+)(MR+) 504.2.

Example 120 Preparation of1-(5-nitro-3-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine

Following the procedure of Example 103(f), except substituting5-nitrofuran-2-carboxaldehyde, the title compound was prepared: MS (ES+)(MH+) 479.1.

The above specification and Examples fully disclose how to make and usethe compounds of the present invention. However, the present inventionis not limited to the particular embodiments described hereinabove, butincludes all modifications thereof within the scope of the followingclaims. The various references to journals, patents and otherpublications which are cited herein comprise the state of the art andare incorporated herein by reference as though fully set forth.

What is claimed is:
 1. A compound according to formula (Ia):

wherein: R¹ is R″, R″C(O), R″C(S), R″SO₂, R″OC(O), R″R′NC(O), orR″R′NC(S); R² is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl; R³ is H, C₂₋₆alkenyl, C₂₋₆alkynyl, Het, Ar or C₁₋₆alkyloptionally substituted by OR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂,N(C═NH)NH₂, Het or Ar; R⁴ is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl; R⁵ is

 Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl, adamantyl-C(O)—, Ar-C(O)—, or Het-C(O)—;R⁶ is R″, R″C(O), R″C(S), R″SO₂, R″OC(O), R″R′NC(O), R″R′NC(S),orR″OC(O)NR′CH(R*)C(O); R⁷ is C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl,Het-C₀₋₆alkyl, Ar-C₀₋₆alkoxy, Het-C₀₋₆alkoxy, or C₁₋₆alkyl optionallysubstituted by OR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂, N(C═NH)NH₂,Het or Ar; R* is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl,Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl; each R′ independently is H, C₁₋₆alkyl,C₂₋₆alkenyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl; each R″ independently isC₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;R′″ is H, C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl; Z is C(O) or CH₂; and n is 1, 2 or 3; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein R⁴ and R′″ are each H.
 3. A compound according to claim1 wherein R³ is C₁₋₆alkyl.
 4. A compound according to claim 3 wherein R³is i-butyl.
 5. A compound according to claim 1 wherein Y is NR¹R², inwhich R² is H and R¹ is R″C(O) or R″OC(O), and R″ in said R¹ group isC₁₋₆alkyl, Ar-C₀₋₆alkyl or Het-C₀₋₆alkyl.
 6. A compound according toclaim 5 wherein R″ in said R¹ group is tert-butyl,


7. A compound according to claim 1 wherein n is 1 or
 2. 8. A compoundaccording to claim 7 wherein n is
 1. 9. A compound according to claim 1wherein R⁵ is benzyl or

 in which R′ is H, R⁷ is C₁₋₆alkyl, R⁶ is R″OC(O) and Z is CH₂.
 10. Acompound according to claim 9 wherein, in said R⁵ group, R⁷ is i-butyland R″ is benzyl.
 11. A compound according to claim 1 of the formula(Ib):


12. A compound according to claim 1 of the formula (Ic):


13. A compound which is:3-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;1-benzyl-3-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;3-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;1-benzyl-3-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;1-benzyl-(3R)-[[N^(α)-(2-naphthyl)acetyl-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3R)-[[N^(α)-(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3R)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3R)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(2-naphthyl)acetyl-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(3-isoquinolinecarbonyl(-L-leucinyl]amino]-pyrrolidine;1-benzyl-4-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-piperidine;1-benzyl-4-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-piperidine;1-benzyl-4-[[N^(α)-(benzyloxycarbonyl)-L-leucinyl]amino]-piperidine;1-[3-(2-pyridyl)phenyl[-2-ethyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-[3-(2-pyridyl)phenyl[-2-ethyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-[3-(2-pyridyl)phenyl[-2-ethyl-(3S)-[[N^(α)-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-[3-(2-pyridyl)phenyl[-2-ethyl-(3R)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-[3-(2-pyridyl)phenyl[-2-ethyl-(3R)-[[N^(α)-(2-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-[3-(2-pyridyl)phenyl[-2-ethyl-(3R)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(1-adamantanecarbonyl)-(3R)-[[N^(α)-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(1-adamantanecarbonyl)-(3S)-[[N^(α)-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;(3R)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(benzothiazole-6-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(indole-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(4-fluorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(4-methoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(3,4-dichlorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(4-biphenylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3R)-[[N^(α)-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(benzothiazole-6-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(indole-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(4-fluorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(4-methoxybenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(3,4-dichlorobenzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(4-biphenylcarbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N-^(α)-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;(3S)-[[N^(α)-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-1-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;1-(4-phenyl)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenyl)benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenyl)benzyl-(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenyl)benzyl-(3S)-[[N^(α)-(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-phenyl)ethyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-phenyl)ethyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-phenyl)ethyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-phenyl)ethyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-phenyl)ethyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-phenyl)ethyl-(3S)-[[N^(α)-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine;1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine1-(4-phenoxy)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-fluoro)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-fluoro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-fluoro)benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-cyano)benzyl-(3S)-[[N^(α)-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-cyano)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine;1-benzyl-(3S)-[[N^(α)-(3-(2-dimethylaminoethoxy)-4-methoxybenzoyl)-L-leucinyl]amino]-pyrrolidine;1-(4-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-(N,N-dimethylamino)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-methoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-carboxymethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3,4-methylenedioxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-naphthyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-indolyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(1-naphthyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-quinolinyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-pyrrolyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-pyridyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-acetamido)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-cyano)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-fluoro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-phenoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-chloro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-trifluoromethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-trifluoromethyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-(3-(N,N-dimethylamino)propoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(4-(isopropyl)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-benzofuranyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-(3-methylbenzo[b]thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(2-nitro)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;-(3-thiophenyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;1-(3,4-dimethoxy)benzyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;or1-(5-nitro-3-furanyl)methyl-(3S)-[[N^(α)-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 15. A method of inhibiting acysteine protease which comprises administering a compound according toclaim
 1. 16. A method according to claim 15 wherein the cysteineprotease is cathepsin K.
 17. A method of inhibiting bone loss whichcomprises administering a compound according to claim
 1. 18. A method oftreating osteoporosis which comprises administering a compound accordingto claim
 1. 19. A method of treating gingival or peridontal diseasewhich comprises administering a compound according to claim
 1. 20. Amethod of treating a disease characterized by excessive cartilage ormatrix degradation which comprises administering a compound according toclaim
 1. 21. A method according to claim 20 wherein said disease isosteoarthritis or rheumatoid arthritis.
 22. A process for preparing acompound of the formula (Ia) as defined in claim 1, which processcomprises: reacting a compound of the formula (II):

or a salt thereof, wherein R′″, R³, R⁴, R⁵ and n are as defined informula (I) of claim 1, with any reactive functional groups protected,with: (a) R″C(O)Cl, in which R″ is as defined in formula (I) of claim 1;or (b) R″C(O)OH, in which R″ is as defined in formula (I) of claim 1, inthe presence of EDC and HOBT; or (c) R″C(O)H, in which R″ is as definedin formula (I) of claim 1, followed by reduction; or (d) R″OC(O)Cl, inwhich R″ is as defined in formula (I) of claim 1, in the presence ofbase; or (e) R″SO₂Cl, in which R″ is as defined in formula (I) of claim1, in the presence of base; and thereafter removing any protectinggroups and optionally forming a pharmaceutically acceptable salt.
 23. Acompound according to formula (II):

wherein: R³ is H, C₂₋₆alkenyl, C₂₋₆alkynyl, Het, Ar or C₁₋₆alkyloptionally substituted by OR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂,N(C═NH)NH₂, Het or Ar; R⁴ is H, C₁₋₆alkyl, C₂₋₆alkenyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl; R⁵ is

 Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl, adamantyl-C(O)—, Ar-C(O)—, Het-C(O)— or;R⁶ is R″, R″C(O), R″C(S), R″SO₂, R″OC(O), R″R′NC(O), R″R′NC(S),orR″OC(O)NR′CH(R*)C(O); R⁷ is C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl,Het-C₀₋₆alkyl, Ar-C₀₋₆alkoxy, Het-C₀₋₆alkoxy, or C₁₋₆alkyl optionallysubstituted by OR′, SR′, NR′₂, N(R′)C(O)OR″, CO₂R′, CO₂NR′₂, N(C═NH)NH₂,Het or Ar; R* is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl,Ar-C₀₋₆alkyl, Het-C₀₋₆alkyl; each R′ independently is H, C₁₋₆alkyl,C₂₋₆alkenyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl; each R″ independently isC₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆-alkyl, Ar-C₀₋₆alkyl, or Het-C₀₋₆alkyl;R′″ is H, C₁₋₆alkyl, C₃₋₆cycloalkyl-C₀₋₆alkyl, Ar-C₀₋₆alkyl, orHet-C₀₋₆alkyl; Z is C(O) or CH₂; and n is 1, 2 or 3; or apharmaceutically acceptable salt thereof.